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Lewis TC, Hotchkis P, Wong A, Lamaina V, Fitzpatrick E, Stiefel A, Ohanian J, Schnier JR, Lesko M, Rudym D, Natalini JG, Angel LF. Comparison of Early Conversion to LCP-Tacrolimus (ENVARSUS XR) to Immediate-Release Tacrolimus in Lung Transplant Recipients. Clin Transplant 2025; 39:e70159. [PMID: 40294109 DOI: 10.1111/ctr.70159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/30/2025]
Abstract
Tacrolimus is highly effective at preventing allograft rejection and prolonging survival after lung transplantation. However, erratic pharmacokinetics may limit efficacy and predispose to greater adverse effects. We conducted a prospective, open-label trial of lung transplant recipients who underwent early conversion (within 30 days) to LCP tacrolimus (LCPT, n = 40) and compared first-year outcomes to an historical control of patients who remained on immediate-release tacrolimus (IRT, n = 24). Subjects were converted 1:1 from IRT to LCPT. The first dose of LCPT overlapped with the last morning dose of IRT. Conversion to LCPT occurred at a median of 17.5 [IQR 12-25] days. The conversion dose ratio was 1.0 mg:mg [IQR 0.75-1.50] at 14 days. At 1 year, there were no differences between LCPT and IRT in the incidence of biopsy-proven (12.5% vs. 25.0%, p = 0.30) or clinically treated (20.0% vs. 25.0%, p = 0.64) acute cellular rejection. However, the severity of any biopsy-proven rejection was significantly higher in the IRT cohort (27.5% vs. 54.2%, p = 0.03). Although not achieving statistical significance, de novo donor-specific antibodies were more commonly observed in the LCPT group (20.0% vs. 4.2%, p = 0.14). Despite this, the incidence of antibody-mediated rejection (7.5% vs. 0.0%, p = 0.29) and early-onset chronic lung allograft dysfunction (7.5% vs. 9.1%, p = 1.00) were similar. The incidence of chronic kidney disease stage 4 or greater at 1-year was similar (7.5% vs. 12.5%, p = 0.66). In conclusion, early conversion to LCPT was feasible and similarly efficacious to IRT in a cohort of lung transplant recipients. Trial Registration: ClinicalTrials.gov identifier: NCT04420195.
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Affiliation(s)
- Tyler C Lewis
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Perry Hotchkis
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Adrian Wong
- Department of Pharmacy, NYU Langone Health, New York, New York, USA
| | - Victoria Lamaina
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | | | - Avital Stiefel
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Juliana Ohanian
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Joseph R Schnier
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, NYU Langone Health, New York, New York, USA
| | - Melissa Lesko
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Darya Rudym
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Jake G Natalini
- Transplant Institute, NYU Langone Health, New York, New York, USA
| | - Luis F Angel
- Transplant Institute, NYU Langone Health, New York, New York, USA
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Yokota H, Akamine Y, Hatakeyama H, Kagaya H, Sakamoto S, Saito M, Takeda M, Sato K, Nakayama K, Kikuchi M. Effect of isavuconazole on the concentration of tacrolimus in a patient with genotype CYP3A5*1/*3: a case report. J Pharm Health Care Sci 2025; 11:20. [PMID: 40083032 PMCID: PMC11905633 DOI: 10.1186/s40780-025-00427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/03/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Azole antifungals are the standard treatment for pulmonary mycosis, which may develop during long-term immunotherapy for kidney transplant. Isavuconazole (ISCZ) is a cytochrome P450 (CYP) 3 A inhibitor that has a risk of interacting with the immunosuppressive drug tacrolimus (TAC). We report a case of simple pulmonary aspergilloma with renal dysfunction due to increased trough levels of TAC after ISCZ coadministration. CASE PRESENTATION A male in his 60s was treated with TAC 3.0 mg/day orally to prevent graft rejection after kidney transplantation. He received a loading dose of ISCZ 600 mg/day orally for two days, followed by a maintenance dose of 200 mg/day for simple pulmonary aspergilloma. The TAC trough concentration increased markedly from 2.4 to 9.9 ng/mL on day 6 after coadministration. The creatinine level increased from 0.70 to 1.08 mg/dL, suggesting renal dysfunction due to TAC. Subsequently, the TAC dosage was reduced, leading to a decreased blood TAC concentration and improved renal function. The patient's genotype was CYP3A5*1/*3. CONCLUSIONS In the early stages of ISCZ treatment, the blood TAC concentration is higher, and CYP3A5 polymorphisms may partially explain the extent of this interaction. We recommend more careful monitoring of TAC and serum creatinine levels for approximately one week after ISCZ administration.
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Affiliation(s)
- Hayato Yokota
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yumiko Akamine
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Harumi Hatakeyama
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hideaki Kagaya
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Sho Sakamoto
- Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Mitsuru Saito
- Department of Urology, Akita University Graduate School of Medicine, Akita, Japan
| | - Masahide Takeda
- Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Kazuhiro Sato
- Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Katsutoshi Nakayama
- Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Masafumi Kikuchi
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
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Balhara A, Tsang YP, Unadkat JD. Cannabidiol and Δ9-tetrahydrocannabinol induce drug-metabolizing enzymes, but not transporters, in human hepatocytes: Implications for predicting complex cannabinoid-drug interactions. Drug Metab Dispos 2025; 53:100037. [PMID: 40009936 DOI: 10.1016/j.dmd.2025.100037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/16/2024] [Accepted: 12/23/2024] [Indexed: 02/28/2025] Open
Abstract
Cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) can inhibit multiple CYPs and UGTs in vivo and/or in vitro. CBD, but not THC, is also a time-dependent inhibitor of CYP3A, CYP1A2, and CYP2C19. We showed that a single 640 mg oral dose of CBD inhibits oral midazolam plasma clearance by 56%, whereas others found no interaction of chronic CBD with midazolam. These data can be explained if chronic CBD induces CYP3A enzymes. To investigate if CBD or THC induces CYP enzymes or transporters, we treated 4 lots of human hepatocytes for 72 hours with in vivo relevant concentrations of CBD (42 nM, 420 nM) or THC (250 nM, 700 nM). Then, mRNA expression and CYP activity were measured using quantitative polymerase chain reaction and liquid chromatography-tandem mass spectrometry, respectively. CYP3A4 mRNA was significantly induced to 7.3-, 11.1-, and 3.3-fold by CBD (420 nM) and 14.8-, 5.9-, and 3.1-fold by THC (700 nM) in 3 of the 4 lots. CYP3A activity was significantly induced 3.39- and 3.28-fold by low (42 nM) and 2.4- and 2.3-fold by high (420 nM) CBD concentrations, respectively, in 2 lots, and 2.3-fold by THC (700 nM) in 1 lot. Rifampin (10 μM) significantly induced CYP3A mRNA and activity across all lots. CBD (420 nM) significantly induced CYP1A2 and CYP2B6 mRNA (but not activity) in 2 lots. No significant induction of other CYPs, UGTs, or transporters was observed. Incorporation of CBD Emax and EC50 of CYP3A4 mRNA induction (without scaling by rifampin mRNA induction) into a CBD physiologically-based pharmacokinetic model successfully captured the lack of the observed chronic CBD-midazolam drug interaction. SIGNIFICANCE STATEMENT: Time-dependent inhibition and induction of CYP3A enzymes by cannabidiol (CBD) is a plausible explanation for the significant CBD-midazolam pharmacokinetic interaction after single-dose CBD administration and the absence of such an interaction after multiple-dose CBD administration.
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Affiliation(s)
- Ankit Balhara
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Yik Pui Tsang
- Department of Pharmaceutics, University of Washington, Seattle, Washington
| | - Jashvant D Unadkat
- Department of Pharmaceutics, University of Washington, Seattle, Washington.
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Fernández-Alarcón B, Nolberger O, Vidal-Alabró A, Rigo-Bonnin R, Grinyó JM, Melilli E, Montero N, Manonelles A, Coloma A, Favà A, Codina S, Cruzado JM, Colom H, Lloberas N. Guiding the starting dose of the once-daily formulation of tacrolimus in " de novo" adult renal transplant patients: a population approach. Front Pharmacol 2024; 15:1456565. [PMID: 39364055 PMCID: PMC11447946 DOI: 10.3389/fphar.2024.1456565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/23/2024] [Indexed: 10/05/2024] Open
Abstract
Aims The once-daily extended-release tacrolimus formulation (ER-Tac) has demonstrated similar efficacy and safety to the twice-daily immediate-release formulation (IR-Tac), but few population-based pharmacokinetic models have been developed in de novo kidney transplant patients to optimize doses. Therefore, this study aimed i) at developing a population pharmacokinetic model for ER-Tac in de novo adult kidney transplant patients ii) and identifying genetic factors and time-varying covariates predictive of pharmacokinetic variability to guide tacrolimus dosage during the early post-transplant period. Methods A total of 1,067 blood tacrolimus concentrations from 138 kidney transplant patients were analyzed. A total of 29 out of 138 patients were intensively sampled for 24 h on the day 5 post-transplantation; meanwhile, for the remaining patients, concentrations were collected on days 5, 10, and 15 after transplantation. Tacrolimus daily doses and genetic and demographic characteristics were retrieved from the medical files. Biochemistry time-varying covariates were obtained on different days over the pharmacokinetic (PK) study. A simultaneous PK analysis of all concentrations was carried out using the non-linear mixed-effects approach with NONMEM 7.5. Results A two-compartment model with linear elimination and delayed absorption best described the tacrolimus pharmacokinetics. Between-patient variability was associated with oral blood clearance (CL/F) and the central compartment distribution volume (Vc/F). Tacrolimus concentrations standardized to a hematocrit value of 45% significantly improved the model (p < 0.001). This method outperformed the standard covariate modeling of the hematocrit-blood clearance relationship. The effect of the CYP3A5 genotype was statistically (p < 0.001) and clinically significant on CL/F. The CL/F of patients who were CYP3A5*1 carriers was 51% higher than that of CYP3A5*1 non-carriers. Age also influenced CL/F variability (p < 0.001). Specifically, CL/F declined by 0.0562 units per each increased year from the value estimated in patients who were 60 years and younger. Conclusion The 36% between-patient variability in CL/F was explained by CYP3A5 genotype, age, and hematocrit. Hematocrit standardization to 45% explained the variability of tacrolimus whole-blood concentrations, and this was of utmost importance in order to better interpret whole-blood tacrolimus concentrations during therapeutic drug monitoring. The dose requirements of CYP3A5*/1 carriers in patients aged 60 years or younger would be highest, while CYP3A5*/1 non-carriers older than 60 years would require the lowest doses.
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Affiliation(s)
- Beatriz Fernández-Alarcón
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Oscar Nolberger
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Anna Vidal-Alabró
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Raul Rigo-Bonnin
- Biochemistry Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Josep M. Grinyó
- Medicine Unit, Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
| | - Edoardo Melilli
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Nuria Montero
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Anna Manonelles
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Ana Coloma
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Alex Favà
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Sergi Codina
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Josep M. Cruzado
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
| | - Helena Colom
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Nuria Lloberas
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, Barcelona, Spain
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Khayatan D, Lemberg DA, Day AS. The Role of Topical Tacrolimus in the Management of Inflammatory Bowel Disease: A Comprehensive Review. J Clin Med 2024; 13:5518. [PMID: 39337004 PMCID: PMC11432474 DOI: 10.3390/jcm13185518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Management of ulcerative colitis and Crohn's disease, the main subtypes of inflammatory bowel disease (IBD), focuses on the induction and maintenance of remission. Tacrolimus, a member of a group of drugs termed calcineurin inhibitors, may have a role in the medical management of IBD when given either systemically or topically. This review aimed to evaluate the available data focusing on the use of topical tacrolimus in the management of IBD. Reports of the use of topical tacrolimus in IBD were extracted from databases up to 31 May 2024. Topical tacrolimus therapy appears to have reasonable efficacy in the induction and maintenance of remission in patients with refractory IBD, with an acceptable safety profile. Overall, the available data are supportive of the use of topical tacrolimus in selected patients. Further comparative clinical studies are required to more fully delineate the role of this drug.
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Affiliation(s)
- Danial Khayatan
- Department of Dermatology, Columbia University Irving Medical Center, New York, NY 10032, USA;
| | - Daniel A. Lemberg
- Paediatric Gastroenterology, Sydney Children’s Hospital, Randwick, Sydney 2031, Australia;
| | - Andrew S. Day
- Paediatric Gastroenterology, Sydney Children’s Hospital, Randwick, Sydney 2031, Australia;
- Department of Paediatrics, University of Otago Christchurch, Christchurch 8011, New Zealand
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Sekar V, Vedhachalam D, Vb A, Sivaraman S, Janakarajan V, Sethuraman S, Shiroor SG, Geoffroy JMM. Combating Alcohol Adduct Impurity in Immunosuppressant Drug Product Manufacturing: A Scientific Investigation for Enhanced Process Control. Pharm Res 2024; 41:983-1006. [PMID: 38561580 DOI: 10.1007/s11095-024-03695-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 03/21/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE This research aims to elucidate critical impurities in process validation batches of tacrolimus injection formulations, focusing on identification and characterization of previously unreported impurity at RRT 0.42, identified as the tacrolimus alcohol adduct. The potential root causes for the formation of new impurity was determined using structured risk assessment by cause and effect fishbone diagram. The primary objective was to propose mitigation plan and demonstrate the control of impurities with 6 month accelerated stability results in development batches. METHODS The investigation utilizes method validation and characterization studies to affirm the accuracy of quantifying the tacrolimus alcohol adduct. The research methodology employed different characterization techniques like rotational rheometer, ICP‒MS, MALDI-MS, 1H NMR, 13C NMR, and DEPT-135 NMR for structural elucidation. Additionally, the exact mass of the impurity is validated using electrospray ionization mass spectra. RESULTS Results indicate successful identification and characterization of the tacrolimus alcohol adduct. The study further explores the transformation of Tacrolimus monohydrate under various conditions, unveiling the formation of Tacrolimus hydroxy acid and proposing the existence of a novel degradation product, the Tacrolimus alcohol adduct. Six-month data from development lots utilizing Manufacturing Process II demonstrate significantly lower levels of alcohol adducts. CONCLUSIONS Manufacturing Process II, selectively locates Tacrolimus within the micellar core of HCO-60, this prevent direct contact of ethanol with Tacrolimus which minimizes impurity alcohol adduct formation. This research contributes to the understanding of tacrolimus formulations, offering ways to safeguard product integrity and stability during manufacturing and storage.
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Affiliation(s)
- Vasanthakumar Sekar
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113.
| | - Devarajan Vedhachalam
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113
| | - ArunKumar Vb
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113
| | - Sivananthan Sivaraman
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113
| | - Venkatakrishnan Janakarajan
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113
| | - Sai Sethuraman
- Pfizer Healthcare India Private Limited, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 8th Floor, Block C, IIT Madras Research Park, Kanagam Road, Taramani, Chennai, India, 600113
| | - Sandeep G Shiroor
- Pfizer, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 375 North Field Drive, Lake Forest, Illinois, 60045, USA
| | - Jean-Marie M Geoffroy
- Pfizer, Medicinal Sciences-Pharmaceutical Sciences Small Molecules, Pfizer Research & Development, 375 North Field Drive, Lake Forest, Illinois, 60045, USA
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Mohammed Ali Z, Meertens M, Fernández B, Fontova P, Vidal-Alabró A, Rigo-Bonnin R, Melilli E, Cruzado JM, Grinyó JM, Colom H, Lloberas N. CYP3A5*3 and CYP3A4*22 Cluster Polymorphism Effects on LCP-Tac Tacrolimus Exposure: Population Pharmacokinetic Approach. Pharmaceutics 2023; 15:2699. [PMID: 38140040 PMCID: PMC10747255 DOI: 10.3390/pharmaceutics15122699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/24/2023] [Accepted: 11/26/2023] [Indexed: 12/24/2023] Open
Abstract
The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed, using NONMEM v7.5, from full PK profiles from a clinical study (n = 30) and trough concentrations (C0) from patient follow-up (n = 68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterized in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time-lagged first-order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by two transit compartments and a mean transit time of 3.02 h. Inter-individual variability was associated with CL/F, Vc/F, and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p < 0.001). Genetic polymorphism of CYP3A5 and a cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion, a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of the inter-individual variability associated with apparent elimination clearance. Considering this covariate in the initial dose estimation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments.
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Affiliation(s)
- Zeyar Mohammed Ali
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy, University of Barcelona, 08007 Barcelona, Spain
| | - Marinda Meertens
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy, University of Barcelona, 08007 Barcelona, Spain
| | - Beatriz Fernández
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy, University of Barcelona, 08007 Barcelona, Spain
| | - Pere Fontova
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
| | - Anna Vidal-Alabró
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
| | - Raul Rigo-Bonnin
- Biochemistry Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain;
| | - Edoardo Melilli
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
| | - Josep M. Cruzado
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
| | - Josep M. Grinyó
- Department of Clinical Sciences, Medicine Unit, University of Barcelona, 08007 Barcelona, Spain;
| | - Helena Colom
- Biopharmaceutics and Pharmacokinetics Unit, Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, School of Pharmacy, University of Barcelona, 08007 Barcelona, Spain
| | - Nuria Lloberas
- Nephrology Department, Hospital Universitari de Bellvitge-IDIBELL, 08908 Barcelona, Spain; (Z.M.A.); (M.M.); (B.F.); (P.F.); (A.V.-A.); (E.M.); (J.M.C.)
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Garg R, Garg A. Tacrolimus loaded nanostructured lipid carriers using Moringa oleifera seed oil: design, optimization and in-vitro evaluations. J Microencapsul 2023; 40:502-516. [PMID: 37366651 DOI: 10.1080/02652048.2023.2231075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 06/22/2023] [Indexed: 06/28/2023]
Abstract
The proposed research aims to develop Tacrolimus-loaded nanostructured lipid carriers (TAC-loaded NLCs) to overcome poor aqueous solubility and dissolution rate to enhance its oral absorption. A central composite design was used to optimise the amount of Poloxamer 188 and D-α-Tocopherol-polyethylene-glycol-succinate (TPGS). The optimised TAC-loaded NLCs contain stearic acid (250 mg), Moringa oleifera (MO) seed oil (50 mg), TAC (Tacrolimus: 10 mg), TPGS (60 mg), and Poloxamer 188 (1% w/v) with a mean diameter of 393.3 ± 29.68 nm, a zeta potential of -18.3 ± 6.19 mV, high entrapment efficiency (92.12 ± 1.14% w/w), and desirability (0.989). TAC-loaded NLCs showed ∼12 times higher drug dissolution efficiency, while in-vitro anti-inflammatory studies showed ∼1.8 times lower IC50 (half-maximal inhibitory concentration) than TAC suspension. The lyophilised TAC-loaded NLCs were found to be stable after 3 months. Thus, the present study concludes the successful encapsulation of TAC in NLCs made of stearic acid and MO seed oil.
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Affiliation(s)
- Rajat Garg
- Institute of Pharmaceutical Research, GLA University, NH-2 Mathura Delhi Road, P.O-Chaumuhan, Mathura, India
| | - Anuj Garg
- Institute of Pharmaceutical Research, GLA University, NH-2 Mathura Delhi Road, P.O-Chaumuhan, Mathura, India
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An S, Lee S, Rhu J, Kim JM, Choi GS, Joh JW. Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients. J Pediatr Surg 2023; 58:2054-2058. [PMID: 37277238 DOI: 10.1016/j.jpedsurg.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/21/2023] [Accepted: 05/07/2023] [Indexed: 06/07/2023]
Abstract
BACKGROUND Nonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. METHODS We screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. RESULTS One hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. CONCLUSIONS Conversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. LEVEL OF EVIDENCE Level IV.
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Affiliation(s)
- SungHyo An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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10
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Kolonko A, Słabiak-Błaż N, Pokora P, Piecha G, Więcek A. Intestinal Permeability in Patients Early after Kidney Transplantation Treated with Two Different Formulations of Once-Daily Tacrolimus. Int J Mol Sci 2023; 24:ijms24098344. [PMID: 37176050 PMCID: PMC10179169 DOI: 10.3390/ijms24098344] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/26/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Adequate tacrolimus blood exposure is crucial in the early post-renal transplant period and a gut epithelial barrier integrity may play a role. We prospectively investigated several markers of intestinal permeability in recent kidney transplant recipients (KTRs) treated with different tacrolimus extended-release formulations. Within each of the 49 KTR pairs that received grafts from the same donor, an early randomized conversion was performed from twice-daily (Prograf) to once-daily tacrolimus formulation: Advagraf or Envarsus. Plasma zonulin, calprotectin, circulating lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (FABP-2), and CD-14 levels were measured. There was no difference in the recipient age, dialysis vintage, BMI, and residual diuresis between Advagraf and Envarsus groups. FABP-2 and LPS levels were significantly associated with tacrolimus trough level, 3-h level, and area under the curve (AUC) in the Envarsus but not in the Advagraf group. AUC was independently increased by LPS and decreased by age, FABP-2 concentration, and the use of Envarsus formulation as compared with Advagraf. Functional changes of gastrointestinal tract in patients treated with Envarsus may influence intestinal tacrolimus absorption to a greater extent than in Advagraf-treated KTRs and may lead to inadequate variability of tacrolimus exposure early after kidney transplantation.
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Affiliation(s)
- Aureliusz Kolonko
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Natalia Słabiak-Błaż
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Patrycja Pokora
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, 40-027 Katowice, Poland
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11
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Cholbi Vives E, Espí Reig J, Cruz Sánchez A, Moreno Maestre E, Ventura Galiano A, Ramos Escorihuela D, Ramos Cebrián M, González-Calero Borrás P, Beneyto Castelló I, Hernández Jaras J. Comparative Study of 2 Extended-Release Tacrolimus Formulations in Kidney Transplantation. Transplant Proc 2022; 54:2434-2438. [PMID: 36334963 DOI: 10.1016/j.transproceed.2022.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 08/30/2022] [Accepted: 10/01/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND During the 1900s, tacrolimus became the mainstay immunosuppressive agent to prevent rejection after kidney transplant. Subsequently, an extended-release tacrolimus (ER-Tac) formulation was developed to improve adherence, and its generic version has been marketed over the last years. This study examines the differences in efficacy and safety between the generic ER-Tac (Conferoport) and the reference brand-name drug (Advagraf). METHODS Prospective, randomized and parallel single-center study (May 2020 to June 2021) with 52 kidney transplant recipients who were randomly assigned to 1 of the following groups: study group (Conferoport, n = 31) and control group (Advagraf, n = 21). The variables of interest were collected and analyzed to compare tacrolimus efficacy and safety between them. Demographic characteristics of the patients and clinical donor data were homogeneous in both groups (P > .05). RESULTS No statistically significant differences were found among treatments regarding dosage used, levels, creatinine, and proteinuria (P > .05), with these variables presenting a downward trend during follow-up and, consequently, the improvement of graft function. Analyses also revealed the absence of differences concerning the incidence of acute rejection and intrapatient variability (coefficient of variation) throughout the first year of evolution between both formulations (P > .05). A total of 5 graft losses occurred, 2 resulting from patient death. CONCLUSIONS In our experience, we found no significant differences between the measured parameters in relation to the efficacy and safety profile of both drugs, with generic ER-Tac being an alternative comparable with the reference brand-name ER-Tac.
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Affiliation(s)
- Ester Cholbi Vives
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
| | - Jordi Espí Reig
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
| | | | - Elena Moreno Maestre
- IIS La Fe - Medical Research Institute Hospital La Fe, Hospital Universitario La Fe, Valencia, Spain
| | - Ana Ventura Galiano
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
| | - David Ramos Escorihuela
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
| | - María Ramos Cebrián
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
| | | | - Isabel Beneyto Castelló
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain.
| | - Julio Hernández Jaras
- Kidney Transplant Unit, Department of Nephrology, Hospital Universitario La Fe, Valencia, Spain
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12
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Rendina M, Paoletti E, Labarile N, Marra A, Iannone A, Castellaneta A, Bussalino E, Ravera M, Schena A, Castellaneta NM, Barone M, Simone S, Gesualdo L, Di Leo A. HCV-positive kidney transplant patients treated with direct-acting antivirals maintain stable medium-term graft function despite persistent reduction in tacrolimus trough levels. Ther Adv Chronic Dis 2022; 13:20406223221117975. [PMID: 36147292 PMCID: PMC9486264 DOI: 10.1177/20406223221117975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 07/19/2022] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND/AIM Direct-acting antivirals (DAAs) have improved the treatment of HCV-positive kidney transplant recipients (KTRs). However, their medium-term follow-up effects on graft function are conflicting. This study aimed to analyze how the interplay between DAAs, calcineurin inhibitors (CNI), and HCV eradication impacts 12-month kidney graft function. METHODS This double-center retrospective study with a prospective follow-up enrolled 35 KTRs with HCV treated with DAAs for 12 weeks. We compared three parameters: estimated glomerular filtration rate (eGFR), 24-h proteinuria, and CNI trough levels at three time points: baseline, end of treatment (EOT), and 12 months later. RESULTS Kidney allograft function remained stable when comparing baseline and 12-month post-treatment values of eGFR (60.7 versus 57.8 ml/min; p = 0.28) and 24-h proteinuria (0.3 versus 0.2 g/24 h; p = 0.15), while tacrolimus (Tac) trough levels underwent a statistically significant decline (6.9 versus 5.4 ng/ml; p = 0.004). Using an ongoing triple Tac-based maintenance therapy as a conservative measure, a dose escalation of Tac was applied only in seven patients. No variation in CyA and mTOR levels was detected. CONCLUSION DAA therapy is safe and effective in HCV-positive KTRs. It also produces a persistent significant reduction in Tac trough levels that does not influence graft function at 12 months.
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Affiliation(s)
- Maria Rendina
- Gastroenterology and Digestive Endoscopy,
University Hospital, Bari, Italy
| | - Ernesto Paoletti
- Nephrology, Dialysis, and Transplantation,
University of Genova and Policlinico San Martino, Genova, Italy
| | - Nunzia Labarile
- Gastroenterology Unit, National Institute of
Gastroenterology IRCCS “Saverio de Bellis’, Research Hospital, Castellana
Grotte, 70013 Bari, Italy
| | - Antonella Marra
- Gastroenterology and Digestive Endoscopy,
University Hospital, Bari, Italy
| | - Andrea Iannone
- Gastroenterology and Digestive Endoscopy,
University Hospital, Bari, Italy
| | | | - Elisabetta Bussalino
- Nephrology, Dialysis, and Transplantation,
University of Genova and Policlinico San Martino, Genova, Italy
| | - Maura Ravera
- Nephrology, Dialysis, and Transplantation,
University of Genova and Policlinico San Martino, Genova, Italy
| | - Antonio Schena
- Nephrology, Dialysis and Transplantation,
University of Bari, Bari, Italy
| | | | - Michele Barone
- Gastroenterology and Digestive Endoscopy,
University Hospital, Bari, Italy
| | - Simona Simone
- Nephrology, Dialysis and Transplantation,
University of Bari, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation,
University of Bari, Bari, Italy
| | - Alfredo Di Leo
- Gastroenterology and Digestive Endoscopy,
University Hospital, Bari, Italy
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13
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Micó-Carnero M, Zaouali MA, Rojano-Alfonso C, Maroto-Serrat C, Ben Abdennebi H, Peralta C. A Potential Route to Reduce Ischemia/Reperfusion Injury in Organ Preservation. Cells 2022; 11:2763. [PMID: 36078175 PMCID: PMC9455584 DOI: 10.3390/cells11172763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 08/29/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The pathophysiological process of ischemia and reperfusion injury (IRI), an inevitable step in organ transplantation, causes important biochemical and structural changes that can result in serious organ damage. IRI is relevant for early graft dysfunction and graft survival. Today, in a global context of organ shortages, most organs come from extended criteria donors (ECDs), which are more sensitive to IRI. The main objective of organ preservation solutions is to protect against IRI through the application of specific, nonphysiological components, under conditions of no blood or oxygen, and then under conditions of metabolic reduction by hypothermia. The composition of hypothermic solutions includes osmotic and oncotic buffering components, and they are intracellular (rich in potassium) or extracellular (rich in sodium). However, above all, they all contain the same type of components intended to protect against IRI, such as glutathione, adenosine and allopurinol. These components have not changed for more than 30 years, even though our knowledge of IRI, and much of the relevant literature, questions their stability or efficacy. In addition, several pharmacological molecules have been the subjects of preclinical studies to optimize this protection. Among them, trimetazidine, tacrolimus and carvedilol have shown the most benefits. In fact, these drugs are already in clinical use, and it is a question of repositioning them for this novel use, without additional risk. This new strategy of including them would allow us to shift from cold storage solutions to cold preservation solutions including multitarget pharmacological components, offering protection against IRI and thus protecting today's more vulnerable organs.
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Affiliation(s)
- Marc Micó-Carnero
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | - Mohamed Amine Zaouali
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carlos Rojano-Alfonso
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
| | | | - Hassen Ben Abdennebi
- Laboratory of Human Genome and Multifactorial Diseases (LR12ES07), Faculty of Pharmacy, University of Monastir, Monastir 5000, Tunisia
| | - Carmen Peralta
- Institut of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
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14
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Francke MI, Visser WJ, Severs D, de Mik-van Egmond AME, Hesselink DA, De Winter BCM. Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients. Eur J Clin Pharmacol 2022; 78:1273-1287. [PMID: 35567629 PMCID: PMC9283366 DOI: 10.1007/s00228-022-03323-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/15/2022] [Indexed: 12/03/2022]
Abstract
PURPOSE A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. METHODS Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. RESULTS In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = - 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. CONCLUSION The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual's tacrolimus dose requirement after transplantation.
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Affiliation(s)
- M I Francke
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Rg-527, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands.
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, MC, Rotterdam, The Netherlands.
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands.
| | - W J Visser
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands
- Department of Internal Medicine, Division of Dietetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - D Severs
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Rg-527, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - A M E de Mik-van Egmond
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands
| | - D A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Room Rg-527, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - B C M De Winter
- Erasmus MC Transplant Institute, Rotterdam, The Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, MC, Rotterdam, The Netherlands
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, The Netherlands
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15
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Tiankanon K, Kerr SJ, Thongthip S, Udomkarnjananun S, Sodsai P, Vorasittha A, Panumatrassamee K, Takkavatakarn K, Tungsanga K, Eiam-Ong S, Praditpornsilpa K, Avihingsanon Y, Townamchai N. Tacrolimus dose adjustment is not necessary in dose to dose conversion from a twice daily to a prolonged release once daily dose form. Sci Rep 2022; 12:10051. [PMID: 35710816 PMCID: PMC9203451 DOI: 10.1038/s41598-022-14317-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 06/06/2022] [Indexed: 11/09/2022] Open
Abstract
Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and Ctrough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m2. The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of Ctrough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of Ctrough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target Ctrough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of Ctrough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC0-24 regardless of CYP3A5 genotypic polymorphism. However, the Ctrough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002).
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Affiliation(s)
- Kanitha Tiankanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Stephen J Kerr
- Biostatistics Excellence Centre, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Siriwan Thongthip
- Maha Chakri Sirindhorn Clinical Research Center, Chulalongkorn University, Bangkok, Thailand
| | - Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Renal Immunology and Renal Transplant Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pimpayao Sodsai
- Center of Excellence in Immunology and Immune-Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Athaya Vorasittha
- Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kamol Panumatrassamee
- Division of Urology, Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kullaya Takkavatakarn
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kriang Tungsanga
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Somchai Eiam-Ong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Kearkiat Praditpornsilpa
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Yingyos Avihingsanon
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.,Renal Immunology and Renal Transplant Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natavudh Townamchai
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand. .,Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Bangkok, Thailand. .,Renal Immunology and Renal Transplant Research Unit, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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16
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Samer A, Almehmadi F, Krimly A, Alrajhi A. Tacrolimus-Induced Diffuse Coronary Artery Spasm. Cureus 2022; 14:e25748. [PMID: 35812568 PMCID: PMC9270072 DOI: 10.7759/cureus.25748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
Prinzmetal angina, also known as vasospastic angina, is defined as an intermittent focal or diffuse coronary artery narrowing, which is often associated with transient ST-segment elevation on an electrocardiogram. Also, it could be associated with an atherosclerotic lesion at the site of the spasm. Vasospastic angina might be induced by medications, most commonly with cocaine and other examples which include catecholamines such as epinephrine, norepinephrine, isoproterenol, dopamine, and dobutamine. Parasympathomimetic agents include acetylcholine, methacholine, and pilocarpine. It is rarely caused by tacrolimus. The clinical evaluation includes an electrocardiogram and echocardiogram. The confirmed diagnosis is done by coronary angiography. Cardiac catheterization is indicated in such cases to rule out coronary artery disease.
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17
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Løhde LW, Bentzon A, Kornblit BT, Roos P, Fink-Jensen A. Possible Tacrolimus-Related Neuropsychiatric Symptoms: One Year After Allogeneic Hematopoietic Cell Transplantation: A Case Report. CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2022; 15:11795476221087053. [PMID: 35342316 PMCID: PMC8941686 DOI: 10.1177/11795476221087053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 02/21/2022] [Indexed: 11/17/2022]
Abstract
Tacrolimus is a calcineurin inhibitor (CNI), an immunosuppressive agent used to
prevent graft versus host disease following allogeneic hematopoietic cell
transplantation (HCT). Side-effects of tacrolimus treatment include
neuropsychiatric symptoms, for example, affective disturbances, psychosis, and
akinetic mutism. The onset of side-effects is independent of tacrolimus blood
concentration and can occur years after treatment initiation. To our knowledge,
case-reports describing tacrolimus-induced neuropsychiatric symptoms following
HCT are sparse. This article reports the case of a 60-year-old woman with T-cell
prolymphocytic leukemia, who developed memory loss, affective disturbances, and
delusions, 1-year after HCT, and tacrolimus treatmentinitiation. Upon hospital
admission, she was motionless and mute, albeit easily roused. The routine
physical examination was without pathological findings. Blood work and
microbiological analyses of blood and cerebrospinal fluid were normal. The
neuroimaging showed chronic structural changes without relation to the debut of
neuropsychiatric symptoms. Tacrolimus was discontinued on suspicion of
tacrolimus-induced neuropsychiatric symptoms. The patient recovered within
48 hours of discontinuation. She was switch to prednisone treatment, and there
has been no reemergence of neuropsychiatric symptoms since.
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Affiliation(s)
| | | | | | - Peter Roos
- Department of Neurology and Neuroscience, Rigshospitalet, Denmark
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18
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Tsakiridou G, O'Dwyer PJ, Margaritis A, Box KJ, Vertzoni M, Kalantzi L, Reppas C. On the usefulness of four in vitro methodologies in screening for product related differences in tacrolimus exposure after oral administration of amorphous solid dispersions with modified release characteristics in the fasted state. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2021.102990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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19
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Herden U, Sterneck M, Buchholz BM, Achilles EG, Ott A, Fischer L. A single-center, open-label, randomized cross-over study to evaluate the pharmacokinetics and bioavailability of once-daily prolonged-release formulations of tacrolimus in de novo liver transplant recipients. Immun Inflamm Dis 2021; 9:1771-1780. [PMID: 34559956 PMCID: PMC8589356 DOI: 10.1002/iid3.537] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The narrow therapeutic window of tacrolimus (Tac) requires intense drug monitoring to achieve adequate efficacy while minimizing dose-related toxicities. Once-daily formulations of Tac (LCP-Tac and PR-Tac) have been recently designed for higher bioavailability and a more consistent exposure over time, as opposed to the twice-daily, administered immediate-release formulation of Tac (IR-Tac). METHODS This single-center, open-label, randomized cross-over pharmacokinetic (PK) study compares extended-release LCP-Tac with the prolonged-release formulation of tacrolimus (PR-Tac) in adult de novo liver transplant recipients. Eligible patients were screened and randomized 1:1 to the two treatment arms up to 30 days after liver transplantation. Patients were administered either LCP-Tac or PR-Tac for 14 days followed by another 14-day time interval of the other once-daily Tac medication. A 24hr-PK profile was obtained at the end of each time interval. RESULTS Nine patients (45%) completed the study resulting in a total of 18 Tac PK profiles. Overall, the profile of the mean concentrations indicated a flattened kinetic of LCP-Tac compared to PR-Tac, especially in the first 3 h after drug intake. The average cumulative dose per day to achieve equivalent trough levels was approximately 25% lower for LCP-Tac (8.7 mg) than for PR-Tac (11.7 mg). LCP-Tac resulted in a longer tmax and fewer peak-to-trough fluctuations compared to PR-Tac. CONCLUSION Despite methodological weaknesses that limit the conclusions, we have found a more consistent drug exposure for LCP-Tac in de novo LT recipients. LCP-Tac demonstrated a greater bioavailability compared to PR-Tac.
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Affiliation(s)
- Uta Herden
- Department of Visceral TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Martina Sterneck
- Department of MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Bettina M. Buchholz
- Department of Visceral TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Eike G. Achilles
- Department of Visceral TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Armin Ott
- Institute of Medical Informatics, Statistics and EpidemiologyTechnische Universität MünchenMunichGermany
| | - Lutz Fischer
- Department of Visceral TransplantationUniversity Medical Center Hamburg‐EppendorfHamburgGermany
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20
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Henin E, Govoni M, Cella M, Laveille C, Piotti G. Therapeutic Drug Monitoring Strategies for Envarsus in De Novo Kidney Transplant Patients Using Population Modelling and Simulations. Adv Ther 2021; 38:5317-5332. [PMID: 34515977 DOI: 10.1007/s12325-021-01905-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 08/26/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients. METHODS The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles. RESULTS The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity. CONCLUSIONS A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.
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Affiliation(s)
| | - Mirco Govoni
- Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy
| | - Massimo Cella
- Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy
| | | | - Giovanni Piotti
- Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy.
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21
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Malik S, Hamer R, Shabir S, Youssouf S, Morsy M, Rashid R, Waqar S, Ghouri N. Effects of fasting on solid organ transplant recipients during Ramadan - a practical guide for healthcare professionals. Clin Med (Lond) 2021; 21:e492-e498. [PMID: 38594852 DOI: 10.7861/clinmed.2021-0250] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Fasting in the month of Ramadan is an obligatory act for healthy adult Muslims. It requires abstinence from food and drink from dawn to sunset. Although there are exemptions from fasting, many patients are keen to fulfil what they see as a religious obligation, even if this may be against medical advice in some cases. Solid organ transplant (SOT) recipients often ask healthcare professionals for advice on fasting. Studies on the effect of fasting in transplant patients have all been done in the Middle East and North Africa where the average fasting duration is between 12 and 14 hours. In comparison, in temperate regions in the summer, fasting duration can be as long as 20 hours. Fasting when patients have to take immunosuppression 12 hours apart with little time variation poses unique challenges. In this review, current literature is reviewed, and a decision-making tool has been developed to assist clinicians in discussing the risks of fasting in transplant recipients, with consideration also given to circumstances such as the COVID-19 pandemic. Our review highlights that SOT recipients wishing to fast should undergo a thorough risk assessment, ideally 3 months before Ramadan. They may require medication changes and a plan for regular monitoring of graft function and electrolytes in order to fast safely. Recommendations have been based on risk tiers (very high risk, high risk and low/moderate risk) established by the International Diabetes Federation and the Diabetes and Ramadan International Alliance. Patients in the 'very high risk' and 'high risk' categories should be encouraged to explore alternative options to fasting such as winter fasting or Fidyah. Those in the 'low/moderate' category may be able to cautiously fast with guidance from their clinician. Prior to the commencement of Ramadan, all patients must receive up-to-date education on sick-day rules, instructions on when to terminate their fast or abstain from fasting.
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Affiliation(s)
- Shafi Malik
- University Hospitals Coventry and Warwickshire NHS Trust, UK, and honorary clinical lecturer, University of Leicester, Leicester, UK.
| | - Rizwan Hamer
- University Hospitals Coventry and Warwickshire NHS Trust, UK
| | | | | | - Mohamed Morsy
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | | | | | - Nazim Ghouri
- University of Glasgow, Glasgow, UK, and consultant physician in diabetes, endocrinology and general medicine, Queen Elizabeth University Hospital, Glasgow, UK
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22
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Tanaka R, Suzuki Y, Watanabe H, Fujioka T, Hirata K, Shin T, Ando T, Ono H, Tatsuta R, Mimata H, Maruyama T, Itoh H. Association of CYP3A5 polymorphisms and parathyroid hormone with blood level of tacrolimus in patients with end-stage renal disease. Clin Transl Sci 2021; 14:2034-2042. [PMID: 34058078 PMCID: PMC8504850 DOI: 10.1111/cts.13065] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/24/2021] [Accepted: 04/02/2021] [Indexed: 12/02/2022] Open
Abstract
Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end‐stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact‐PTH (iPTH) level with blood tacrolimus concentration in patients with end‐stage renal disease just before kidney transplantation. Forty‐eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co‐administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.
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Affiliation(s)
- Ryota Tanaka
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Yosuke Suzuki
- Department of Medication Use Analysis and Clinical Research, Meiji Pharmaceutical University, Tokyo, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takashi Fujioka
- Laboratory of Medical Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kenshiro Hirata
- Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
| | - Toshitaka Shin
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Tadasuke Ando
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Hiroyuki Ono
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Ryosuke Tatsuta
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
| | - Hiromitsu Mimata
- Department of Urology, Faculty of Medicine, Oita University, Oita, Japan
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Itoh
- Department of Clinical Pharmacy, Oita University Hospital, Oita, Japan
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23
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Kim CS, Mathew AP, Vasukutty A, Uthaman S, Joo SY, Bae EH, Ma SK, Park IK, Kim SW. Glycol chitosan-based tacrolimus-loaded nanomicelle therapy ameliorates lupus nephritis. J Nanobiotechnology 2021; 19:109. [PMID: 33865397 PMCID: PMC8052756 DOI: 10.1186/s12951-021-00857-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Faslpr mutation were also treated with HGC vehicle and used as healthy controls. Results Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone. Conclusion Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice. ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-00857-w.
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Affiliation(s)
- Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea.,Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Ansuja Pulickal Mathew
- Department of Biomedical Sciences, BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun, 58128, Republic of Korea
| | - Arathy Vasukutty
- Department of Biomedical Sciences, BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun, 58128, Republic of Korea
| | - Saji Uthaman
- Department of Polymer Science and Engineering, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Soo Yeon Joo
- Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea.,Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea.,Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea
| | - In-Kyu Park
- Department of Biomedical Sciences, BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun, 58128, Republic of Korea.
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea. .,Department of Internal Medicine, Chonnam National University Hospital, Gwangju, Republic of Korea.
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24
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Gao GF, Ashtikar M, Kojima R, Yoshida T, Kaihara M, Tajiri T, Shanehsazzadeh S, Modh H, Wacker MG. Predicting drug release and degradation kinetics of long-acting microsphere formulations of tacrolimus for subcutaneous injection. J Control Release 2021; 329:372-384. [PMID: 33271202 DOI: 10.1016/j.jconrel.2020.11.055] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 11/23/2020] [Accepted: 11/27/2020] [Indexed: 12/13/2022]
Abstract
Today, tacrolimus represents a cornerstone of immunosuppressive therapy for liver and kidney transplants and remains subject of preclinical and clinical investigations, aiming at the development of long-acting depot formulations for subcutaneous injection. One major challenge arises from establishing in vitro-in vivo correlations due to the absence of meaningful in vitro methods predictive for the in vivo situation, together with a strong impact of multiple kinetic processes on the plasma concentration-time profile. In the present approach, two microsphere formulations were compared with regards to their in vitro release and degradation characteristics. A novel biorelevant medium provided the physiological ion and protein background. Release was measured using the dispersion releaser technology under accelerated conditions. A release of 100% of the drug from the carrier was achieved within 7 days. The capability of the in vitro performance assay was verified by the level A in vitro-in vivo correlation analysis. The contributions of in vitro drug release, drug degradation, diffusion rate and lymphatic transport to the absorption process were quantitatively investigated by means of a mechanistic modelling approach. The degradation rate, together with release and diffusion characteristics provides an estimate of the bioavailability and therefore can be a guide to future formulation development.
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Affiliation(s)
- Ge Fiona Gao
- Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany
| | - Mukul Ashtikar
- Institute of Pharmaceutical Technology, Goethe University, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
| | - Ryo Kojima
- Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan
| | - Takatsune Yoshida
- Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan
| | - Masanori Kaihara
- Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan
| | - Tomokazu Tajiri
- Astellas Pharma Inc., 180, Ozumi, Yaizu-shi, Shizuoka 425-0072, Japan
| | - Saeed Shanehsazzadeh
- National University of Singapore, Department of Pharmacy, 5 Science Drive 2, Singapore 117545, Singapore
| | - Harshvardhan Modh
- National University of Singapore, Department of Pharmacy, 5 Science Drive 2, Singapore 117545, Singapore
| | - Matthias G Wacker
- National University of Singapore, Department of Pharmacy, 5 Science Drive 2, Singapore 117545, Singapore.
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25
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Zhang Z, Zhang Y, Yu H, Rong S, Gao H, Meng L, Dai J, Pan H, Chang D. Spherical carrier amplification strategy for electrochemical immunosensor based on polystyrene-gold nanorods @L-cysteine/MoS2 for determination of tacrolimus. Talanta 2020; 220:121321. [DOI: 10.1016/j.talanta.2020.121321] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/11/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022]
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26
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van Gelder T, Etsouli O, Moes DJ, Swen JJ. Comparison of the Impact of Pharmacogenetic Variability on the PK of Slow Release and Immediate Release Tacrolimus Formulations. Genes (Basel) 2020; 11:genes11101205. [PMID: 33076474 PMCID: PMC7602647 DOI: 10.3390/genes11101205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/10/2020] [Accepted: 10/14/2020] [Indexed: 12/18/2022] Open
Abstract
Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme (CYP3A5 *1/*3 or *1/*1) compared to nonexpressers (CYP3A5*3/*3). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the CYP3A5 expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected.
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27
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Tenório JR, Tuma M, Martins F, Ortega KL, Cristelli M, Gallottini M. Diagnosis and management of oral ulcerations associated with mycophenolate mofetil in kidney transplantation. SPECIAL CARE IN DENTISTRY 2020; 40:605-610. [PMID: 32950040 DOI: 10.1111/scd.12522] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 11/28/2022]
Abstract
AIMS The final diagnosis of oral mucosal ulcerations in solid organ transplant recipients represents a challenge. We describe a unique case of oral ulceration related to mycophenolate mofetil (MMF) toxicity, 11 years after kidney transplantation, whose dose reduction was sufficient to resolve it. METHODS AND RESULTS A 54-year-old female patient, who underwent kidney transplantation 11 years ago, presents multiple ulcers on the buccal mucosa bilaterally, soft palate and tongue dorsum, for 8 months, with moderate pain. The diagnosis of oral ulcerations associated with MMF therapy was assumed by excluding infection and malignancy diagnosis. After MMF dose reduction, the oral ulcers healed utterly. CONCLUSIONS MMF toxicity manifested as oral ulcers. Reduction or discontinuation of MMF therapy should be considered in a patient with refractory oral ulcers and a negative workup for other causes.
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Affiliation(s)
- Jefferson R Tenório
- Special Care Dentistry Center, School of Dentistry of the University of São Paulo, São Paulo, Brazil
| | - Marina Tuma
- Special Care Dentistry Center, School of Dentistry of the University of São Paulo, São Paulo, Brazil
| | - Fabiana Martins
- Special Care Dentistry Center, School of Dentistry of the University of São Paulo, São Paulo, Brazil.,Dental School, University of Santo Amaro, São Paulo, Brazil
| | - Karem L Ortega
- Special Care Dentistry Center, School of Dentistry of the University of São Paulo, São Paulo, Brazil
| | - Marina Cristelli
- Department of Nephrologist, Oswaldo Ramos Foundation Kidney Hospital, São Paulo, Brazil
| | - Marina Gallottini
- Special Care Dentistry Center, School of Dentistry of the University of São Paulo, São Paulo, Brazil
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28
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Gantar K, Škerget K, Mochkin I, Bajc A. Meeting Regulatory Requirements for Drugs with a Narrow Therapeutic Index: Bioequivalence Studies of Generic Once-Daily Tacrolimus. Drug Healthc Patient Saf 2020; 12:151-160. [PMID: 32982466 PMCID: PMC7489937 DOI: 10.2147/dhps.s256455] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 08/15/2020] [Indexed: 12/21/2022] Open
Abstract
Despite growing clinical confidence in generics and their potential to reduce long-term healthcare costs, the transplant community have had real concerns about the use of generic immunosuppressants. One such immunosuppressant is tacrolimus, a cornerstone of lifelong treatment for patients who have undergone a solid organ transplant. Tacrolimus has a narrow therapeutic index (NTI), giving rise to questions about the potential for clinically relevant altered drug exposure. Its use in transplant patients also gives rise to questions about the most discriminative subject population for bioequivalence studies. The recognised need for stringent criteria to support approval of generic drugs with an NTI led the European Medicines Association and Health Canada to provide detailed information on requirements for bioequivalence studies and introduce tighter bioequivalence limits for these drugs, including tacrolimus. The aim of this article is to illustrate how regulatory guidance is implemented during the clinical development of generic immunosuppressants, using a generic, once-daily prolonged-release formulation of tacrolimus as an example.
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Affiliation(s)
- Kaja Gantar
- Sandoz Development Center Slovenia, Lek Pharmaceuticals d.d, Ljubljana1526, Slovenia
| | - Katja Škerget
- Sandoz Development Center Slovenia, Lek Pharmaceuticals d.d, Ljubljana1526, Slovenia
| | - Ilya Mochkin
- Sandoz International GmbH, Holzkirchen83607, Germany
| | - Aleksander Bajc
- Sandoz Development Center Slovenia, Lek Pharmaceuticals d.d, Ljubljana1526, Slovenia
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29
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Chen L, Li C, Huo N, Mishuk AU, Hansen RA, Harris I, Kiptanui Z, Qian J. Oral generic tacrolimus initiation and substitution in the Medicaid population: a new user cohort study. Curr Med Res Opin 2020; 36:1533-1540. [PMID: 32644886 DOI: 10.1080/03007995.2020.1793750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE Although existing studies have compared clinical efficacy and pharmacokinetics of generic with brand tacrolimus, little is known about generic tacrolimus utilization patterns or factors predicting generic substitution. This study examines associations between patient-level factors and generic tacrolimus initiation or substitution among new users of oral generic or brand-name tacrolimus. METHODS This new user retrospective cohort study identified 374 beneficiaries who initiated generic or brand tacrolimus treatment, using 100% Medicaid administrative claims data from 11 states in 2011-2012. Outcomes were generic tacrolimus initiation and substitution within 12 months of treatment initiation. Multivariable logistic regression and Cox proportional hazards models were used to identify factors associated with generic tacrolimus initiation and substitution. RESULTS Two-thirds of oral tacrolimus new users initiated generic tacrolimus. Patients who were older age and black were significantly more likely to initiate generic tacrolimus (adjusted odds ratio [AOR] = 1.02, 95% confidence interval [CI] = 1.001-1.03; AOR = 2.54, 95% CI = 1.40-4.62; respectively). Patients with more concomitant prescriptions, more comorbidities, or higher initial daily dosage had significantly lower likelihoods of initiating generic tacrolimus (AOR = 0.93, 95% CI = 0.87-0.99; AOR = 0.87, 95% CI = 0.77-0.99; AOR = 0.96, 95% CI = 0.93-0.993). Among brand tacrolimus new users, 23.6% substituted with generics within 12 months, and an addition of prior hospitalization or unit of initial daily dosage increment was associated with 35% (subdistribution hazard ratio [SHR] = 1.35, 95% CI = 1.02-1.76) or 2% (SHR = 1.02, 95% CI = 1.00-1.04) increase in likelihood of generic substitution, respectively. CONCLUSIONS Understanding associations between patient-level factors with generic tacrolimus initiation and substitution could help practitioners and policymakers monitor treatment effect and facilitate generic tacrolimus utilization.
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Affiliation(s)
- Li Chen
- Department of Medicine, Center for Computational Biology and Bioinformatics, Indiana University, Indianapolis, IN, USA
| | - Chao Li
- Department of Health Outcomes Research and Policy, Auburn University, Auburn, AL, USA
| | - Nan Huo
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Ahmed Ullah Mishuk
- Department of Health Outcomes Research and Policy, Auburn University, Auburn, AL, USA
| | - Richard A Hansen
- Department of Health Outcomes Research and Policy, Auburn University, Auburn, AL, USA
| | | | | | - Jingjing Qian
- Department of Health Outcomes Research and Policy, Auburn University, Auburn, AL, USA
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30
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Leino AD, Pai MP. Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection. Clin Pharmacokinet 2020; 59:1317-1334. [PMID: 32720300 DOI: 10.1007/s40262-020-00923-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Calcineurin inhibitors, the primary immunosuppressive therapy used to prevent alloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.
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Affiliation(s)
- Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA.
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Bezerra LS, Santos-Veloso MAO, Oliveira SBLD, Dias AAP, Carvalho-Filho ÂTD, Gonzaga-Neto PP, Melo PSVD. Tacrolimus therapeutic efficacy in post-liver transplant patients with Cytochrome P450 3A5 (CYP3A5) genetic polymorphisms. Rev Col Bras Cir 2020; 47:e20202384. [PMID: 32578817 DOI: 10.1590/0100-6991e-20202384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 12/31/2019] [Indexed: 11/22/2022] Open
Abstract
Genetic polymorphisms of CYP3A5 have been pointed out as factors that influenciates tacrolimus immunosuppressive efficacy in post liver transplant patients. This study aims to review the literature on the influence of cytochrome P450 3A5 (CYP3A5) genetic polymorphisms of tacrolimus in post-liver transplant patients. This study is a literature review. A combination of the descriptors "tacrolimus", "liver transplant", "cytochrome P-450 CYP3A inhibitors" and "genetic polymorphism" were used in the databases PubMed, Cochrane Library, Scopus and Scielo, being evaluated only studies between 2009 and 2019 in English, Portuguese or Spanish. A total of six studies, each from a different population were summarized. Initially, the pharmacological aspects of tacrolimus were discussed, including details on its pharmacodynamics, pharmacokinetics and toxicity After that, we analyzed the studies that correlates CYP3A5 genetic polymorphisms and tacrolimus efficacy, including the ethnical specifications and the general limittions of the studies. The CYP3A5 polymorphisms have pointed to alterations in the metabolism of tacrolimus according to the ethnic and populational genotype, specially the *1 and *3*3 alleles, reflecting in the need for dose adjustment and also in post liver transplant rejection.
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Affiliation(s)
- Lucas Soares Bezerra
- Universidade Federal de Pernambuco, Programa de Pós-Graduação em Inovação Terapêutica - Recife - PE - Brasil
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Jorgenson MR, Descourouez JL, Brady BL, Bowman L, Hammad S, Kaiser TE, Laub MR, Melaragno JI, Park JM, Chandran MM. Alternatives to immediate release tacrolimus in solid organ transplant recipients: When the gold standard is in short supply. Clin Transplant 2020; 34:e13903. [DOI: 10.1111/ctr.13903] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/25/2020] [Accepted: 05/07/2020] [Indexed: 12/28/2022]
Affiliation(s)
| | | | - Bethany L. Brady
- Pharmacy Department Indiana University Health University Hospital Indianapolis IN USA
| | - Lyndsey Bowman
- Department of Pharmacy Tampa General Hospital Tampa FL USA
| | - Sara Hammad
- Department of Pharmacy University of Maryland Medical Center Baltimore MD USA
| | - Tiffany E. Kaiser
- Department of Pharmacy University of Cincinnati Medical Center Cincinnati OH USA
| | - Melissa R. Laub
- Department of Pharmacy Augusta University Medical Center Augusta GA USA
| | | | - Jeong M. Park
- Department of Clinical Pharmacy University of Michigan College of Pharmacy Ann Arbor MI USA
| | - Mary M. Chandran
- Department of Pharmacy Children's Hospital of Colorado Aurora CO USA
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Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients. Sci Rep 2020; 10:7542. [PMID: 32371893 PMCID: PMC7200804 DOI: 10.1038/s41598-020-64189-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 04/10/2020] [Indexed: 01/18/2023] Open
Abstract
The development of predictive engines based on pharmacokinetic-physiological mathematical models for personalised dosage recommendations is an immature field. Nevertheless, these models are extensively applied during the design of new drugs. This study presents new advances in this subject, through a stable population of patients who underwent kidney transplantation and were prescribed tacrolimus. We developed 2 new population pharmacokinetic models based on a compartmental approach, with one following the physiologically based pharmacokinetic approach and both including circadian modulation of absorption and clearance variables. One of the major findings was an improved predictive capability for both models thanks to the consideration of circadian rhythms, both in estimating the population and in Bayesian individual customisation. This outcome confirms a plausible mechanism suggested by other authors to explain circadian patterns of tacrolimus concentrations. We also discovered significant intrapatient variability in tacrolimus levels a week after the conversion from a fast-release (Prograf) to a sustained-release formulation (Advagraf) using adaptive optimisation techniques, despite high adherence and controlled conditions. We calculated the intrapatient variability through parametric intrapatient variations, which provides a method for quantifying the mechanisms involved. We present a first application for the analysis of bioavailability changes in formulation conversion. The 2 pharmacokinetic models have demonstrated their capability as predictive engines for personalised dosage recommendations, although the physiologically based pharmacokinetic model showed better predictive behaviour.
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Vadcharavivad S, Saengram W, Phupradit A, Poolsup N, Chancharoenthana W. Once-Daily versus Twice-Daily Tacrolimus in Kidney Transplantation: A Systematic Review and Meta-analysis of Observational Studies. Drugs 2020; 79:1947-1962. [PMID: 31713065 PMCID: PMC6900208 DOI: 10.1007/s40265-019-01217-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tacrolimus is the most commonly prescribed medication in initial immunosuppressive regimens to prevent acute rejection in kidney transplant recipients (KTRs). Tacrolimus was originally available as an immediate-release formulation (IR-Tac) given twice daily. Extended-release tacrolimus (ER-Tac) given once daily was later developed with the expectation of improved medication adherence. Data from observational studies, which compared outcomes between ER-Tac and IR-Tac in different populations of KTRs including those who are unlikely to be enrolled in randomized clinical trials, have been reported. PURPOSE To evaluate the incidence of biopsy-proven acute rejection (BPAR) at 12 months together with other outcomes reported in observational studies among adult KTRs who received ER-Tac compared to IR-Tac. METHODS In accordance with the recommendations of the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology, we systematically reviewed all observational studies that compared clinical outcomes between ER-Tac and IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Scopus, and Web of Science without language restriction. Reference lists were also searched and reviewed. Data were extracted for BPAR, graft survival, patient survival, estimated glomerular filtration rate (eGFR), serum creatinine (Scr), creatinine clearance (CrCl), at different times after kidney transplantation (KT). A meta-analysis was performed to integrate the results from the eligible studies. This study is registered with PROSPERO, number CRD42019135705. RESULTS From the 1401 articles screened, 10 observational studies in KTRs who received tacrolimus were included. The pooled results showed significantly lower BPAR with ER-Tac than with IR-Tac at 12 months post-KT (5 studies, n = 659; RR, 0.69; 95% CI 0.51-0.95; p = 0.02; I2 = 0%). No significant differences in BPAR at other time points after KT were found. Graft survival, patient survival, Scr, and eGFR were comparable between groups at different times over approximately 1 year after transplantation. CONCLUSIONS Based upon currently available evidence in observational studies, 30% lower risk of BPAR was observed in ER-Tac group compared with IR-Tac group at 12 months post-KT, while there was no significant difference in BPAR risk at any other studied time points. No differences in graft- and patient-survival rates and kidney function were found. Given the limitations of observational studies to make causal inference, as well as quality limitations among the included studies, caution should be exercised in interpreting these findings.
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Affiliation(s)
- Somratai Vadcharavivad
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Warangkana Saengram
- Pharmacy Department, Thammasat University Hospital, Pathumthani, 12120, Thailand
| | - Annop Phupradit
- Pharmacy Division, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand
| | - Nalinee Poolsup
- Samrejvittaya School, Aranyaprathet, Sakaeo, 27120, Thailand
| | - Wiwat Chancharoenthana
- Immunology Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Nephrology Research Unit, Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
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Estimation of Blood Sirolimus Concentration Based on Tacrolimus Concentration/Dose Normalized by Body Weight Ratio in Lung Transplant Patients. Ther Drug Monit 2020; 41:615-619. [PMID: 31033859 DOI: 10.1097/ftd.0000000000000649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Sirolimus and tacrolimus require accurate drug dosing based on their target blood levels to produce better clinical outcomes, specifically, the avoidance of drug-induced adverse effects and the maintenance of efficacy. However, because the ideal dose of sirolimus and the schedule for measuring its blood levels are unclear in lung transplant patients, an index is required for estimating sirolimus blood concentrations. The aim of this work is to study the correlation between the trough concentration/dose normalized by body weight (C0/D) ratios of sirolimus and tacrolimus in lung transplant patients. METHODS Thirteen lymphangiomyomatosis patients who underwent lung transplantation and were treated with sirolimus and tacrolimus from February 2015 to July 2018 were divided into 2 groups, one receiving twice-daily (TD, n = 6) and the other once-daily (OD, n = 7) tacrolimus formulations. The correlation between the C0/D ratio of sirolimus and patient background was evaluated using Spearman's rank correlation coefficient. Correlations between sirolimus and tacrolimus C0/D ratios or doses were analyzed by single regression analysis. RESULTS Significant correlations were found between the C0/D ratios of sirolimus and tacrolimus. The regression equations from the initial data of TD and OD groups at steady state were y = 1.880x + 32.636 (adjusted R = 0.743, P = 0.017) and y = 1.684x + 38.816 (adjusted R = 0.919, P < 0.001), respectively. In addition, the regression equations from all data of TD and OD groups were y = 1.883x + 4.170 (adjusted R = 0.546, P < 0.001) and y = 1.950x + 43.188 (adjusted R = 0.898, P < 0.001), respectively. A significant correlation between the dosage of sirolimus and tacrolimus was observed only in the OD group, with relatively low accuracy. CONCLUSIONS Blood sirolimus concentrations can be estimated using the C0/D ratio of tacrolimus, suggesting that the C0/D ratio of tacrolimus is an index of required sirolimus dosage and the frequency of blood sirolimus concentration measurements.
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UniORV, a New Multi-Unit Dosage Form, Improved Biopharmaceutical Properties of Tacrolimus in Rats and Humans. Pharm Res 2020; 37:64. [DOI: 10.1007/s11095-020-02785-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2019] [Accepted: 02/16/2020] [Indexed: 11/25/2022]
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Stifft F, Vandermeer F, Neef C, van Kuijk S, Christiaans MHL. A limited sampling strategy to estimate exposure of once-daily modified release tacrolimus in renal transplant recipients using linear regression analysis and comparison with Bayesian population pharmacokinetics in different cohorts. Eur J Clin Pharmacol 2020; 76:685-693. [DOI: 10.1007/s00228-019-02814-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 12/05/2019] [Indexed: 11/30/2022]
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Fleming JN, Posadas Salas MA, Taber DJ. Dosing Requirements of Extended-Release Tacrolimus (Astagraf XL) in African American Kidney Transplant Recipients Converted from Immediate-Release Tacrolimus (AAAKTRS). Ther Drug Monit 2020; 42:415-420. [PMID: 31913864 DOI: 10.1097/ftd.0000000000000722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND The formal recommendation for converting twice-daily tacrolimus immediate release (IR) to once-daily tacrolimus extended release (ER) is a 1:1 dose conversion. However, more recent clinical analysis has shown that this may not be true; some patients may require a higher dose. In addition, de novo dosing tacrolimus ER has revealed that African Americans require approximately 20%-30% higher doses than Caucasians to achieve similar levels. As a result, this study sought to identify the appropriate dose conversion in the African American kidney transplant population, a population at high risk of rejection. METHODS This was a single-center, prospective, open-label study comparing the difference in dose-normalized trough and total daily dose necessary to reach steady-state therapeutic goal, after conversion from tacrolimus IR to tacrolimus ER, in 25 African American kidney transplant recipients. RESULTS After conversion to tacrolimus ER, there was a significant decrease in dose-normalized trough (C0) (0.44 versus 0.59, P = 0.03). Statistically significant differences were seen in both total daily and weight-based doses, when reported as actual values (15 versus 10 mg and 0.16 versus 0.11 mg/kg, respectively), as well as when standardized to achieve a target tacrolimus C0 of 8 ng/mL (18.1 versus 13.6 mg and 0.17 versus 0.15 mg/kg, respectively). The median standardized dose conversion required was 1.3 [1.0, 1.4], for the overall population. There were no instances of biopsy-proven acute rejection, allograft loss, or study drug discontinuation. CONCLUSIONS This single-center, open-label conversion study demonstrated that there was a statistically and clinically significant decrease in dose-normalized trough after conversion from tacrolimus IR to tacrolimus ER in an African American kidney transplant population and that a 1:1 dose conversion is unlikely to meet therapeutic goals.
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Affiliation(s)
- James N Fleming
- Department of Pharmacy Services, Medical University of South Carolina
| | - Maria A Posadas Salas
- Department of Medicine, Division of Nephrology and Hypertension, Medical University of South Carolina
| | - David J Taber
- Department of Pharmacy, Ralph H Johnson VAMC; and.,Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
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Sánchez Fructuoso A, Ruiz JC, Franco A, Diekmann F, Redondo D, Calviño J, Serra N, Aladrén MJ, Cigarrán S, Manonelles A, Ramos A, Gómez G, González Posada JM, Andrés A, Beneyto I, Muñiz AL, Perelló M, Lauzurica R. Effectiveness and safety of the conversion to MeltDose ® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study. Clin Transplant 2019; 34:e13767. [PMID: 31815310 PMCID: PMC7050537 DOI: 10.1111/ctr.13767] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 11/14/2019] [Accepted: 11/25/2019] [Indexed: 12/24/2022]
Abstract
Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk‐benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice‐daily immediate‐release tacrolimus (IR‐Tac) or once‐daily prolonged‐release tacrolimus (PR‐Tac) to the recent formulation once‐daily MeltDose® extended‐release tacrolimus (LCP‐Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP‐Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre‐conversion (20.8%) to post‐conversion (11.8%, P < .0001). LCP‐Tac generated a cost reduction of 63% compared with PR‐Tac. In conclusion, the conversion strategy to LCP‐Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real‐world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP‐Tac could be potentially advantageous in patients with tacrolimus‐related adverse events.
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Affiliation(s)
| | - Juan Carlos Ruiz
- Nephrology, University Hospital Marqués de Valdecilla, Santander, Spain
| | - Antonio Franco
- Nephrology, University Hospital General, Alicante, Spain
| | - Fritz Diekmann
- Nephrology, University Hospital Clinic, Barcelona, Spain
| | | | | | - Nuria Serra
- Nephrology, Fundación Puigvert, Barcelona, Spain
| | | | | | - Ana Manonelles
- Nephrology, University Hospital Bellvitge, Hospitalet de Llobregat, Spain
| | - Ana Ramos
- Nephrology, Fundación Jiménez Díaz, Madrid, Spain
| | - Gonzalo Gómez
- Nephrology, University Hospital son Espases, Palma de Mallorca, Spain
| | | | - Amado Andrés
- Nephrology, University Hospital Doce de Octubre, Madrid, Spain
| | | | | | - Manel Perelló
- Nephrology, University Hospital Vall de Hebrón, Barcelona, Spain
| | - Ricardo Lauzurica
- Nephrology, University Hospital Germans Trias y Pujol, Badalona, Spain
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Nanga TM, Doan TTP, Marquet P, Musuamba FT. Toward a robust tool for pharmacokinetic-based personalization of treatment with tacrolimus in solid organ transplantation: A model-based meta-analysis approach. Br J Clin Pharmacol 2019; 85:2793-2823. [PMID: 31471970 DOI: 10.1111/bcp.14110] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 07/31/2019] [Accepted: 08/06/2019] [Indexed: 02/07/2023] Open
Abstract
AIMS The objective of this study is to develop a generic model for tacrolimus pharmacokinetics modelling using a meta-analysis approach, that could serve as a first step towards a prediction tool to inform pharmacokinetics-based optimal dosing of tacrolimus in different populations and indications. METHODS A systematic literature review was performed and a meta-model developed with NONMEM software using a top-down approach. Historical (previously published) data were used for model development and qualification. In-house individual rich and sparse tacrolimus blood concentration profiles from adult and paediatric kidney, liver, lung and heart transplant patients were used for model validation. Model validation was based on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness of fit with respect to measured blood concentrations with no indication of bias, and acceptable performance of visual predictive checks. External validation was performed by fitting the model to independent data from 3 external cohorts and remaining previously published studies. RESULTS A total of 76 models were found relevant for meta-model building from the literature and the related parameters recorded. The meta-model developed using patient level data was structurally a 2-compartment model with first-order absorption, absorption lag time and first-time varying elimination. Population values for clearance, intercompartmental clearance, central and peripheral volume were 22.5 L/h, 24.2 L/h, 246.2 L and 109.9 L, respectively. The absorption first-order rate and the lag time were fixed to 3.37/h and 0.33 hours, respectively. Transplanted organ and time after transplantation were found to influence drug apparent clearance whereas body weight influenced both the apparent volume of distribution and the apparent clearance. The model displayed good results as regards the internal and external validation. CONCLUSION A meta-model was successfully developed for tacrolimus in solid organ transplantation that can be used as a basis for the prediction of concentrations in different groups of patients, and eventually for effective dose individualization in different subgroups of the population.
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Affiliation(s)
- Tom M Nanga
- INSERM UMR 1248, Université de Limoges, FHU support, Limoges Cédex, 87025, France
| | - Thao T P Doan
- INSERM UMR 1248, Université de Limoges, FHU support, Limoges Cédex, 87025, France
| | - Pierre Marquet
- INSERM UMR 1248, Université de Limoges, FHU support, Limoges Cédex, 87025, France
| | - Flora T Musuamba
- Federal Agency for Medicines and Health Products, Brussels, Belgium.,Faculté des sciences pharmaceutiques, Université de Lubumbashi, Lubumbashi, Democratic Republic of the Congo
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Dheer D, Gupta R, Singh D, Magotra A, Singh G, Gupta PN, Shankar R. Hyaluronic Acid-Tacrolimus Bioconjugate: Synthesis, Characterization, and Pharmacokinetic Investigation of an Acid-Responsive Macromolecular Prodrug. ACS APPLIED BIO MATERIALS 2019; 2:4728-4736. [DOI: 10.1021/acsabm.9b00423] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Stephens A, Nidetz R, Mesyngier N, Chung MT, Song Y, Fu J, Kurabayashi K. Mass-producible microporous silicon membranes for specific leukocyte subset isolation, immunophenotyping, and personalized immunomodulatory drug screening in vitro. LAB ON A CHIP 2019; 19:3065-3076. [PMID: 31389447 PMCID: PMC6736731 DOI: 10.1039/c9lc00315k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
Widespread commercial and clinical adaptation of biomedical microfluidic technology has been limited in large part due to the lack of mass producibility of polydimethylsiloxane (PDMS) and glass-based devices commonly as reported in the literature. Here, we present a batch-fabricated, robust, and mass-producible immunophenotyping microfluidic device using silicon micromachining processes. Our Si and glass-based microfluidic device, named the silicon microfluidic immunophenotyping assay (SiMIPA), consists of a highly porous (∼40%) silicon membrane that can selectively separate microparticles below a certain size threshold. The device is capable of isolating and stimulating specific leukocyte populations, and allows for measuring their secretion of cell signaling proteins by means of a no-wash homogeneous chemiluminescence-based immunoassay. The high manufacturing throughput (∼170 devices per wafer) makes a large quantity of SiMIPA chips readily available for clinically relevant applications, which normally require large dataset acquisitions for statistical accuracy. With 30 SiMIPA chips, we performed in vitro immunomodulatory drug screening on isolated leukocyte subsets, yielding 5 data points at 6 drug concentrations. Furthermore, the excellent structural integrity of the device allowed for samples and reagents to be loaded using a micropipette, greatly simplifying the experimental protocol.
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Affiliation(s)
- Andrew Stephens
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
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Franco A, Más-Serrano P, Balibrea N, Rodriguez D, Javaloyes A, Díaz M, Gascón I, Ramon-Lopez A, Perez-Contreras J, Selva J, Nalda-Molina R. Envarsus, a novelty for transplant nephrologists: Observational retrospective study. Nefrologia 2019; 39:506-512. [PMID: 30850218 DOI: 10.1016/j.nefro.2018.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 11/06/2018] [Accepted: 11/09/2018] [Indexed: 11/29/2022] Open
Abstract
The aim of this study was to evaluate the trough concentrations (Cptrough) and the tacrolimus dosage regimen after the conversion of Prograf or Advagraf to Envarsus (new pharmaceutical form with MeltDose technology that improves the absorption of fat-soluble drugs) in patients with stable renal transplantation, and their renal function. We selected stable renal transplant patients who were converted to Envarsus. Two periods were defined: Baseline and Conversion (Envarsus) and they were stratified according to the pharmaceutical form used in the Baseline period. Sixty-one patients were included (24 with Advagraf and 37 with Prograf), with an average age of 52years. The mean post-transplant time at the time of conversion to Envarsus was 76.3months and the mean follow-up in the Baseline and Conversion period was 10.1months and 11.6months, respectively. In the Prograf and Envarsus group, the Cptrough medians were 6.6 vs 6.4 ng/mL (P=.636), with a mean daily dose that decreased significantly from 3mg to 2mg (P<.001), respectively, maintaining the filtration rate. The median Cptrough values in the Advagraf and Envarsus groups were 5.7ng/mL and 6.3ng/mL (P=.07), with a median daily dose of 7mg and 4mg (P<.001), respectively, and the same renal function. In stable renal transplant patients, the conversion from Advagraf to Envarsus has allowed the dose of tacrolimus to be reduced by 42.9% and, in the case of Prograf, by 33.3%, maintaining similar Cptrough values, without renal function being altered.
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Affiliation(s)
- Antonio Franco
- Servicio de Nefrología, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España.
| | - Patricio Más-Serrano
- Servicio de Farmacia, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España; Área de Farmacia y Tecnología Farmacéutica, Departamento de Ingeniería, Universidad Miguel Hernández de Elche; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Elche, Alicante, España
| | - Noelia Balibrea
- Servicio de Nefrología, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - David Rodriguez
- Servicio de Nefrología, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - Aurora Javaloyes
- Servicio de Farmacia, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - Marcos Díaz
- Servicio de Farmacia, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - Isabel Gascón
- Servicio de Farmacia, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - Amelia Ramon-Lopez
- Área de Farmacia y Tecnología Farmacéutica, Departamento de Ingeniería, Universidad Miguel Hernández de Elche; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Elche, Alicante, España
| | - Javier Perez-Contreras
- Servicio de Nefrología, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España
| | - Juan Selva
- Servicio de Farmacia, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Hospital General Universitario de Alicante, Alicante, España; Área de Farmacia y Tecnología Farmacéutica, Departamento de Ingeniería, Universidad Miguel Hernández de Elche; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Elche, Alicante, España
| | - Ricardo Nalda-Molina
- Área de Farmacia y Tecnología Farmacéutica, Departamento de Ingeniería, Universidad Miguel Hernández de Elche; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-Fundación FISABIO), Elche, Alicante, España
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Gustavsen MT, Midtvedt K, Lønning K, Jacobsen T, Reisaeter AV, De Geest S, Andersen MH, Hartmann A, Åsberg A. Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation - a single-centre open prospective trial. Transpl Int 2019; 32:614-625. [DOI: 10.1111/tri.13412] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 10/19/2018] [Accepted: 02/11/2019] [Indexed: 01/15/2023]
Affiliation(s)
- Marte Theie Gustavsen
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- School of Pharmacy; University of Oslo; Oslo Norway
| | - Karsten Midtvedt
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
| | - Kjersti Lønning
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Faculty of Medicine; Institute of Clinical Medicine; University of Oslo; Oslo Norway
| | | | - Anna Varberg Reisaeter
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Norwegian Renal Registry; Oslo University Hospital, Rikshospitalet; Oslo Norway
| | - Sabina De Geest
- Institute of Nursing Science; University of Basel; Basel Switzerland
- Academic Centre for Nursing and Midwifery; KU-Leuven; Leuven Belgium
| | - Marit Helen Andersen
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Department of Health Sciences; Faculty of Medicine; University of Oslo; Oslo Norway
| | - Anders Hartmann
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Faculty of Medicine; Institute of Clinical Medicine; University of Oslo; Oslo Norway
| | - Anders Åsberg
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- School of Pharmacy; University of Oslo; Oslo Norway
- Norwegian Renal Registry; Oslo University Hospital, Rikshospitalet; Oslo Norway
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Kamar N, Cassuto E, Piotti G, Govoni M, Ciurlia G, Geraci S, Poli G, Nicolini G, Mariat C, Essig M, Malvezzi P, Le Meur Y, Garrigue V, Del Bello A, Rostaing L. Pharmacokinetics of Prolonged-Release Once-Daily Formulations of Tacrolimus in De Novo Kidney Transplant Recipients: A Randomized, Parallel-Group, Open-Label, Multicenter Study. Adv Ther 2019; 36:462-477. [PMID: 30552587 PMCID: PMC6824349 DOI: 10.1007/s12325-018-0855-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING Chiesi Farmaceutici S.p.A.
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Affiliation(s)
- Nassim Kamar
- Departments of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Elisabeth Cassuto
- Unité de Transplantation Rénale, Hôpital Pasteur 2, CHU Nice, Nice, France
| | - Giovanni Piotti
- Kidney and Pancreas Transplantation Unit, University Hospital of Parma, 43121, Parma, Italy
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy
| | - Mirco Govoni
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy.
| | - Giorgia Ciurlia
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy
| | - Silvia Geraci
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy
| | - Gianluigi Poli
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy
| | - Gabriele Nicolini
- Global Clinical Development, Department of Clinical Pharmacology, Chiesi Farmaceutici, Parma, Italy
| | - Christophe Mariat
- CHU Saint-Etienne, Hôpital Nord Avenue Albert Raimond, Saint Priest en Jarez, France
| | - Marie Essig
- Nephrology Unit, CHU Limoges, 2 Avenue Martin Luther King, Limoges, France
| | - Paolo Malvezzi
- Service de Néphrologie, Dialyse, Aphérèses et Transplantation, CHU Grenoble Alpes, Grenoble, France
| | - Yannick Le Meur
- Service de Nephrologie-Transplantation Rénale et Hémodialyse, CHRU Brest, Hôpital de la Cavale Blanche, Brest, France
| | - Valerie Garrigue
- Service de Néphrologie-Transplantation-Dialyse péritonéale CHU Lapeyronie, Montpellier, France
| | - Arnaud Del Bello
- Departments of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Lionel Rostaing
- Service de Néphrologie, Dialyse, Aphérèses et Transplantation, CHU Grenoble Alpes, Grenoble, France
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The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients. Pediatr Nephrol 2019; 34:507-515. [PMID: 30374607 PMCID: PMC6349786 DOI: 10.1007/s00467-018-4117-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/10/2018] [Accepted: 10/11/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Tacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients. METHODS Data were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated. RESULTS In total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations. CONCLUSION A critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.
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Isotope–labeled versus analog internal standard in LC–MS/MS method for tacrolimus determination in human whole blood samples – A compensation of matrix effects. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1104:220-227. [DOI: 10.1016/j.jchromb.2018.11.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/25/2018] [Accepted: 11/27/2018] [Indexed: 12/31/2022]
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Conversion from Twice-Daily Prograf ® to Once-Daily Advagraf ® in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure. Eur J Drug Metab Pharmacokinet 2018; 44:481-492. [PMID: 30471066 DOI: 10.1007/s13318-018-0531-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVES Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf® to once-daily Advagraf® is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf® to Advagraf® and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics. METHODS A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf® to Advagraf® with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24 h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T. RESULTS After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median 224 (range 172-366) vs. 184 (104-347) ng·h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng·h/mL, p = 0.014, n = 18], not among non-expressors [215 (197-290) vs. 217 (129-281) ng·h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng·h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism. CONCLUSION The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf® to Advagraf®. These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients.
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Okumi M, Unagami K, Furusawa M, Kakuta Y, IIzuka J, Takagi T, Shirakawa H, Shimizu T, Omoto K, Inui M, Ishida H, Tanabe K. Once-daily vs twice-daily tacrolimus for de novo living kidney transplantation patients including ABO/HLA compatible and incompatible: A randomized trial. Clin Transplant 2018; 32:e13423. [PMID: 30318624 DOI: 10.1111/ctr.13423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 09/05/2018] [Accepted: 10/09/2018] [Indexed: 11/26/2022]
Abstract
Tacrolimus (TAC) is available as a twice-daily capsule (TAC-BID), once-daily capsule (TAC-QD), and once-daily tablet. Recipients with ABO-incompatible/anti-human leukocyte antigen (HLA)-incompatible transplantation were excluded in previous trials and have thus not been evaluated. We conducted a 5-year trial to determine whether TAC-QD is noninferior to TAC-BID for transplant outcomes. Adults who underwent de novo living kidney transplantation were randomly assigned (62 TAC-QD; 63 TAC-BID). We did not exclude ABO-/HLA- incompatible transplantation. TAC was initiated 7 days preoperatively (0.10 mg/kg/d). Mycophenolate mofetil, methylprednisolone, and basiliximab were administered. The primary endpoint was graft failure (non-censored for death). We performed a noninferiority test. The noninferiority margin was 10% in risk difference. Five-year graft failure rates were 6.5% and 9.5% for TAC-QD and TAC-BID, respectively (noninferiority, P = 0.009). The estimated glomerular filtration rates were similar between the groups (noninferiority, P < 0.001). TAC-QD did not have point estimates of risk difference above the inferiority margin in any assessed endpoints. However, a tendency of interaction was observed between biopsy-proven acute rejection and the follow-up period. In a living kidney transplant population with 40% of patients with ABO/HLA incompatibility, the effect of TAC-QD was not appreciably worse on various clinical transplant outcomes than that of TAC-BID over 5 years.
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Affiliation(s)
- Masayoshi Okumi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kohei Unagami
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Miyuki Furusawa
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoichi Kakuta
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Junpei IIzuka
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Tomokazu Shimizu
- Department of Urology and Transplant Surgery, Toda Chuo General Hospital, Saitama, Japan
| | - Kazuya Omoto
- Department of Urology and Transplant Surgery, Toda Chuo General Hospital, Saitama, Japan
| | - Masashi Inui
- Department of Urology, Yachiyo Medical Center, Tokyo Women's Medical University, Chiba, Japan
| | - Hideki Ishida
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
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Saengram W, Vadcharavivad S, Poolsup N, Chancharoenthana W. Extended release versus immediate release tacrolimus in kidney transplant recipients: a systematic review and meta-analysis. Eur J Clin Pharmacol 2018; 74:1249-1260. [PMID: 29961086 DOI: 10.1007/s00228-018-2512-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 06/22/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE To compare the estimated glomerular filtration rate (eGFR) at 12 months together with other outcomes among adult kidney transplant recipients (KTRs) who received extended release, once daily tacrolimus (ER-Tac) compared to those who received the immediate release, twice daily tacrolimus (IR-Tac) administration. METHODS In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, we systematically reviewed all randomized controlled trials (RCTs) that compared clinical outcomes between ER-Tac versus IR-Tac in KTRs. The systematic searches were conducted on PubMed, EMBASE, Cochrane Register of Controlled Trials, Scopus, Web of Science, and CINAHL without language restriction. The trials registered and reference lists were also searched and reviewed. Data were extracted for eGFR, serum creatinine (Scr), creatinine clearance (CrCl), biopsy-proven acute rejection rate (BPAR), graft survival, and overall patient survival at different times over 24 months after kidney transplant (KT). A meta-analysis was performed to integrate the results from eligible studies. RESULTS From 1145 articles screened, 11 RCTs were included. The pooled results of included RCTs showed no significant difference of eGFR at 12 months between ER-Tac and IR-Tac groups (four trials, n = 1738; mean difference - 0.77 mL/min/1.73 m2, 95% CI: - 2.41 to 0.87; p = 0.56; I2 = 0%). Comparing between the two tacrolimus formulations, there were no significant differences of eGFR, CrCl, Scr, BPAR, graft survival, and patient survival at different times over 4 years after transplantation. CONCLUSIONS Based upon currently available evidences in KTRs, the impact on kidney allograft function appears to be comparable between ER-Tac and IR-Tac.
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Affiliation(s)
- Warangkana Saengram
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Somratai Vadcharavivad
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Nalinee Poolsup
- Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Sanam Chandra Palace campus, Nakhon Pathom, 73000, Thailand
| | - Wiwat Chancharoenthana
- Division of Nephrology and Hypertension, Department of Medicine, Princess Chulabhorn College of Medical Sciences, and Comprehensive Center of Excellence in Organ Transplantation and Research, Chulabhorn Hospital, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
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