|
1
|
Sureshkumar KK, Ryhal R, Nashar K, Daloul R. Mycophenolate-Induced Dysphagia in a Kidney Transplant Recipient. Indian J Nephrol 2025; 35:446-447. [PMID: 40352889 PMCID: PMC12065595 DOI: 10.25259/ijn_680_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 11/22/2024] [Indexed: 05/14/2025] Open
Affiliation(s)
- Kalathil K Sureshkumar
- Division of Nephrology and Hypertension, Medicine Institute, Allegheny General Hospital, Pittsburgh, PA, United States
| | - Robert Ryhal
- Division of Nephrology and Hypertension, Medicine Institute, Allegheny General Hospital, Pittsburgh, PA, United States
| | - Khaled Nashar
- Division of Nephrology and Hypertension, Medicine Institute, Allegheny General Hospital, Pittsburgh, PA, United States
| | - Reem Daloul
- Division of Nephrology and Hypertension, Medicine Institute, Allegheny General Hospital, Pittsburgh, PA, United States
| |
Collapse
|
|
2
|
Mohamed ME, Saqr A, Onyeaghala G, Remmel RP, Staley C, Dorr CR, Teigen L, Guan W, Madden H, Munoz J, Sanchez B, Vo D, El-Rifai R, Oetting WS, Matas AJ, Israni AK, Jacobson PA. Simultaneous Prediction of Area Under the Curves of Mycophenolic Acid and Its Metabolites and Enterohepatic Recirculation in Kidney Transplant Recipients. Ther Drug Monit 2025:00007691-990000000-00348. [PMID: 40315256 DOI: 10.1097/ftd.0000000000001336] [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: 01/28/2025] [Accepted: 03/05/2025] [Indexed: 05/04/2025]
Abstract
BACKGROUND Therapeutic drug monitoring of mycophenolic acid (MPA) is limited due to the requirement for intensive pharmacokinetic sampling to assess the area under the curve (AUC). Limited sampling strategies (LSS) offer a practical alternative; however, enterohepatic recirculation (EHR) affects prediction accuracy and precision. This study is the first to develop LSS models capable of simultaneously predicting the AUC of MPA, its metabolites [mycophenolic acid glucuronide (MPAG) and acyl mycophenolic acid glucuronide (Acyl-MPAG)], and MPA EHR in kidney transplant recipients (KTRs). METHODS Intensive pharmacokinetic sampling was conducted in 84 adult KTRs receiving mycophenolate mofetil. MPA AUC0-12 was calculated, and MPA EHR was determined. During the development of the LSS models, a balanced representation of patients with high and low EHR was ensured. Multiple linear regression was used to develop AUC prediction models for MPA, MPAG, and Acyl-MPAG, as well as an EHR prediction model. The best models were selected based on prediction performance, the highest prediction concordance, and the shortest interval between the first and last samples. RESULTS Three models for AUC0-12 prediction were identified, incorporating 4, 5, and 6 concentration timepoints. The LSS model with 6 concentrations demonstrated the best performance, with excellent prediction concordance (100% for MPA and MPAG, and 93% for Acyl-MPAG). The EHR prediction model included 4 concentrations and exhibited an ∼80% prediction concordance. An online calculator was developed for these models. CONCLUSIONS The developed LSS models simultaneously predict MPA, MPAG, and Acyl-MPAG AUC0-12 using the same timepoints with high accuracy and precision. MPA EHR can be predicted using 4 concentration timepoints. The inclusion of late concentration timepoints is essential for the high predictive performance of LSS models. CLINICAL TRIAL NOTATION clinicaltrials.gov, NCT04953715.
Collapse
Affiliation(s)
- Moataz E Mohamed
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Abdelrahman Saqr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | | | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Christopher Staley
- Department of Surgery, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Casey R Dorr
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
- Division of Nephrology and Hypertension, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Levi Teigen
- Department of Food Science and Nutrition, University of Minnesota, St. Paul, Minnesota
| | - Weihua Guan
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Henry Madden
- Department of Surgery, Clinical Trials Office, University of Minnesota, Minneapolis, Minnesota; and
| | - Julia Munoz
- Department of Surgery, Clinical Trials Office, University of Minnesota, Minneapolis, Minnesota; and
| | - Bryan Sanchez
- Division of Nephrology, University of Texas Medical Branch, Galveston, Texas
| | - Duy Vo
- Division of Nephrology, University of Texas Medical Branch, Galveston, Texas
| | - Rasha El-Rifai
- Division of Nephrology and Hypertension, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Arthur J Matas
- Department of Surgery, School of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Ajay K Israni
- Division of Nephrology, University of Texas Medical Branch, Galveston, Texas
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| |
Collapse
|
|
3
|
Kaye AD, Shah SS, Johnson CD, De Witt AS, Thomassen AS, Daniel CP, Ahmadzadeh S, Tirumala S, Bembenick KN, Kaye AM, Shekoohi S. Tacrolimus- and Mycophenolate-Mediated Toxicity: Clinical Considerations and Options in Management of Post-Transplant Patients. Curr Issues Mol Biol 2024; 47:2. [PMID: 39852117 PMCID: PMC11763814 DOI: 10.3390/cimb47010002] [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: 11/27/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 01/26/2025] Open
Abstract
Tacrolimus and mycophenolate are important immunosuppressive agents used to prevent organ rejection in post-transplant patients. While highly effective, their use is associated with significant toxicity, requiring careful management. Tacrolimus, a calcineurin inhibitor, is linked to nephrotoxicity, neurotoxicity, metabolic disturbances such as diabetes mellitus and dyslipidemia, and cardiovascular complications such as hypertension and arrhythmias. Mycophenolate, a reversible inhibitor of inosine monophosphate dehydrogenase, frequently causes gastrointestinal disturbances, including diarrhea and colitis, as well as hematologic side effects like anemia and leukopenia, which increase infection risk. Therapeutic drug monitoring (TDM) and pharmacogenomics have emerged as essential strategies for mitigating these toxicities. TDM ensures tacrolimus trough levels are maintained within a therapeutic range, minimizing the risks of nephrotoxicity and rejection. Pharmacogenomic insights, such as CYP3A5 polymorphisms, allow for personalized tacrolimus dosing based on individual metabolic profiles. For mycophenolate, monitoring inosine monophosphate dehydrogenase activity provides a pharmacodynamic approach to dose optimization, reducing gastrointestinal and hematologic toxicities. Emerging tools, including dried blood spot sampling and pharmacokinetic modeling, offer innovative methods to simplify monitoring and enhance precision in outpatient settings. Despite their utility, the toxicity profiles of these drugs, including those of early immunosuppressants such as cyclosporine and azathioprine, necessitate further consideration of alternative immunosuppressants like sirolimus, everolimus, and belatacept. Although promising, these newer agents require careful patient selection and further research. Future directions in immunosuppressive therapy include integrating individual pharmacogenetic data to refine dosing, minimize side effects, and improve long-term graft outcomes. This narrative review underscores the importance of personalized medicine and advanced monitoring in optimizing post-transplant care.
Collapse
Affiliation(s)
- Alan D. Kaye
- Departments of Anesthesiology and Pharmacology, Toxicology, and Neurosciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, USA
| | - Shivam S. Shah
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA; (S.S.S.); (C.D.J.); (C.P.D.)
| | - Coplen D. Johnson
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA; (S.S.S.); (C.D.J.); (C.P.D.)
| | - Adalyn S. De Witt
- School of Medicine, Indiana University, 340 W 10th St., Indianapolis, IN 46202, USA
| | - Austin S. Thomassen
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA; (S.S.S.); (C.D.J.); (C.P.D.)
| | - Charles P. Daniel
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA 71103, USA; (S.S.S.); (C.D.J.); (C.P.D.)
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, USA
| | - Sridhar Tirumala
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, USA
| | - Kristin Nicole Bembenick
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, USA
| | - Adam M. Kaye
- Department of Pharmacy Practice, Thomas J. Long School of Pharmacy, University of the Pacific, 751 Brookside Road, Stockton, CA 95207, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA 71103, USA
| |
Collapse
|
|
4
|
Klotsman M, Anderson WH, Wyatt D, Lewis T, Theus N, Santoro D. Treatment of moderate-to-severe canine atopic dermatitis with modified-release mycophenolate (OKV-1001): A pilot open-label, single-arm multicentric clinical trial. Vet Dermatol 2024; 35:652-661. [PMID: 39129671 DOI: 10.1111/vde.13283] [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: 03/13/2024] [Revised: 05/26/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND Mycophenolate is an immunomodulating agent successfully used for the treatment of moderate-to-severe atopic dermatitis (AD) in people. Mycophenolate is an effective steroid-sparing treatment option for use in dogs with inflammatory skin diseases. OBJECTIVE To evaluate whether once-daily modified-release mycophenolate (OKV-1001) is safe and effective for treating moderate-to-severe canine AD. ANIMALS Client-owned atopic dogs (n = 9) were enrolled. MATERIALS AND METHODS In an open-label multicentre pilot study, OKV-1001 (30 mg/kg every 24 h) was given orally for ≤84 days. Concomitant tapering doses of glucocorticoids were administered up to Day (D)28. Clinicians assessed Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) on D0, D14, D28, D56 and D84. Body weight and clinical pathological parameters were measured at baseline and at the end of the study. RESULTS Treatment with OKV-1001 combined with glucocorticoids significantly reduced the severity of AD within two weeks in seven of nine (77.8%) dogs. The mean percentage change from baseline in the CADESI-04 score was 29% (p = 0.009) at D14 (n = 9), 39% (p = 0.008) at D28 (n = 9) and 49% (p = 0.03) at D56 (n = 7) at which point glucocorticoids had been withdrawn. In two dogs the improvement in CADESI-04 was 62% and 23% (respectively) on D84. No significant adverse events including clinical pathological findings were reported. CONCLUSIONS AND CLINICAL RELEVANCE Modified-release mycophenolate (OKV-1001) may represent a promising alternative treatment option for dogs with moderate-to-severe AD. The safety and efficacy profile of OKV-1001 will need to be established in larger, placebo-controlled clinical trials.
Collapse
Affiliation(s)
| | - Wayne H Anderson
- Okava Pharmaceuticals, San Francisco, California, USA
- Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - Tom Lewis
- Dermatology for Animals, Gilbert, Arizona, USA
| | | | - Domenico Santoro
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA
| |
Collapse
|
|
5
|
Brossier C, Jardou M, Janaszkiewicz A, Firoud D, Petit I, Arnion H, Pinault E, Sauvage FL, Druilhe A, Picard N, Di Meo F, Marquet P, Lawson R. Gut microbiota biotransformation of drug glucuronides leading to gastrointestinal toxicity: Therapeutic potential of bacterial β-glucuronidase inhibition in mycophenolate-induced enteropathy. Life Sci 2024; 351:122792. [PMID: 38857657 DOI: 10.1016/j.lfs.2024.122792] [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: 02/09/2024] [Revised: 04/28/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
AIMS Drug-induced enteropathy is often associated with the therapeutic use of certain glucuronidated drugs. One such drug is mycophenolic acid (MPA), a well-established immunosuppressant of which gastrointestinal adverse effects are a major concern. The role of bacterial β-glucuronidase (β-G) from the gut microbiota in MPA-induced enteropathy has recently been discovered. Bacterial β-G hydrolyzes MPAG, the glucuronide metabolite of MPA excreted in the bile, leading to the digestive accumulation of MPA that would favor in turn these adverse events. We therefore hypothesized that taming bacterial β-G activity might reduce MPA digestive exposure and prevent its toxicity. MAIN METHODS By using a multiscale approach, we evaluated the effect of increasing concentrations of MPA on intestinal epithelial cells (Caco-2 cell line) viability, proliferation, and migration. Then, we investigated the inhibitory properties of amoxapine, a previously described bacterial β-G inhibitor, by using molecular dynamics simulations, and evaluated its efficiency in blocking MPAG hydrolysis in an Escherichia coli-based β-G activity assay. The pharmacological effect of amoxapine was evaluated in a mouse model. KEY FINDINGS We observed that MPA impairs intestinal epithelial cell homeostasis. Amoxapine efficiently blocks the hydrolysis of MPAG to MPA and significantly reduces digestive exposure to MPA in mice. As a result, administration of amoxapine in MPA-treated mice significantly attenuated gastrointestinal lesions. SIGNIFICANCE Collectively, these results suggest that the digestive accumulation of MPA is involved in the pathophysiology of MPA-gastrointestinal adverse effects. This study provides a proof-of-concept of the therapeutic potential of bacterial β-G inhibitors in glucuronidated drug-induced enteropathy.
Collapse
Affiliation(s)
- Clarisse Brossier
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Manon Jardou
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Angelika Janaszkiewicz
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Djouher Firoud
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Isy Petit
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Hélène Arnion
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Emilie Pinault
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - François-Ludovic Sauvage
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Anne Druilhe
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Nicolas Picard
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, F-87000 Limoges, France
| | - Florent Di Meo
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France
| | - Pierre Marquet
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France; Department of Pharmacology, Toxicology and Pharmacovigilance, CHU Limoges, F-87000 Limoges, France
| | - Roland Lawson
- Pharmacology & Transplantation (P&T), INSERM U1248, Université de Limoges, F-87000 Limoges, France.
| |
Collapse
|
|
6
|
Quiroz JNC, Villalobos JSG, Pereira JCT. Efficacy and Safety of Mycophenolate Mofetil In De Novo Renal Transplantation in a Retrospective Cohort of Transplant Recipients in Colombia-Esmitren Study. Transplant Proc 2024; 56:297-305. [PMID: 38395659 DOI: 10.1016/j.transproceed.2023.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/21/2023] [Accepted: 12/28/2023] [Indexed: 02/25/2024]
Abstract
BACKGROUND To describe and establish the efficacy and safety of Mycophenolate Mofetil (Micoflavin) in patients with de novo renal transplantation during one-year post-transplant follow-up. As secondary objectives, the behavior of mycophenolic acid (MPA) C0 levels in this population, the relationship between MPA levels and renal function of the grafts, the incidence of acute rejection, and the incidence of adverse effects were evaluated. METHODS A prospective cohort study was conducted on patients who received a first kidney transplant from a deceased donor between March 1, 2021, and February 28, 2022, at the Alma Mater of Antioquia Hospital of the Antioquia's University, in Medellín, Colombia. MPA C0 levels were taken from the patients on days 15, 30, 90, 180, and 360 after the kidney transplantation. RESULTS Patients presented MPA therapeutic levels in the study. The average of the MPA levels in the population was 2.5 µg/mL, with an IQR of 2.13 to 3.32. There were 5 acute rejections (27%), but none of the patients with acute rejection presented subtherapeutic levels of mycophenolate. No significant relationship was observed between mycophenolic acid levels and rejection (P = .255). The patients who completed the study had no gastrointestinal intolerance to mycophenolate, cytomegalovirus infections, or significant hematological complications. CONCLUSIONS MMF (Micoflavin) maintained mycophenolic acid levels C0 within the therapeutic range, was well tolerated and without the presence of significant adverse events, and maintained stable renal function throughout the follow-up period in the population studied.
Collapse
Affiliation(s)
- Jose Nelson Carvajal Quiroz
- Department of Internal Medicine, Faculty of Medicine, University of Antioquia, Medellín, Colombia; Alma Mater of Antioquia Hospital of the Antioquia's University, Medellín, Colombia.
| | | | | |
Collapse
|
|
7
|
Wilson NK, Kataria AD. Immunosuppression in solid organ-transplant recipients and impact on nutrition support. Nutr Clin Pract 2024; 39:109-116. [PMID: 38030572 DOI: 10.1002/ncp.11099] [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: 09/15/2023] [Revised: 10/28/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023] Open
Abstract
A key component to nutrition support is to consider immunosuppressive agents, the interaction with nutrients, and how the side effects of the medications influence nutrition support. The immunosuppression of the solid organ-transplant recipient involves the individualized titration of multiple therapeutic agents to prevent allorecognition and, thus, rejection of the transplanted organ. Induction immunosuppression includes the agents used at the time of transplant to prevent early rejection. Maintenance immunosuppression typically consists of oral medications taken for life. Regular therapeutic monitoring of immunosuppression is necessary to balance the risk of rejection with that of infections and malignancy. In the acute-care setting, multidisciplinary collaboration, including pharmacy and nutrition, is needed to optimize the route of administration, titration, and side effects of immunosuppression. Long-term nutrition management after transplant is also vital to prevent exacerbating adverse effects of immunosuppressive therapies, including diabetes mellitus, hypertension, dyslipidemia, obesity, and bone loss. This review summarizes common immunosuppressive agents currently utilized in solid organ-transplant recipients and factors that may influence decisions on nutrition support.
Collapse
Affiliation(s)
- Nicole K Wilson
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| | - Ann D Kataria
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| |
Collapse
|
|
8
|
Dugbartey GJ, Sener A. Organ Toxicity by Immunosuppressive Drugs in Solid Organ Transplantation. RECENT ADVANCES IN THERAPEUTIC DRUG MONITORING AND CLINICAL TOXICOLOGY 2022:255-271. [DOI: 10.1007/978-3-031-12398-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
9
|
Fukushima K, Lappin M, Legare M, Veir J. A retrospective study of adverse effects of mycophenolate mofetil administration to dogs with immune-mediated disease. J Vet Intern Med 2021; 35:2215-2221. [PMID: 34231261 PMCID: PMC8478029 DOI: 10.1111/jvim.16209] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 06/11/2021] [Accepted: 06/18/2021] [Indexed: 01/20/2023] Open
Abstract
Background Information regarding adverse events (AEs) of mycophenolate mofetil (MMF) is limited. Objectives To evaluate the types and frequency of potential AEs of MMF in dogs with immune‐mediated disease. Animals One hundred thirty‐one dogs treated with MMF for management of suspected immune‐mediated disease. Methods Retrospective study. Medical records were reviewed to find and group suspect AEs in gastrointestinal (GI), hematologic, and other categories. Age, dosage, body weight, and sex were analyzed between dogs with and without AEs by using the Mann‐Whitney U‐test and chi‐squared test. Results The median starting dosage of MMF was 17.5 mg/kg/day (interquartile range [IQR] = 15.1‐20.6 mg/kg/day) and the median treatment duration was 56 days (IQR = 14‐236 days). Mycophenolate mofetil was prescribed for immune‐mediated hemolytic anemia (n = 31), immune‐mediated thrombocytopenia (n = 31), pemphigus foliaceus (n = 15), immune‐mediated polyarthritis (n = 12), and others (n = 42). Overall, potential AEs of MMF were observed in 34 of 131 dogs (GI 24.4% [31/127], neutropenia 4% [3/76], anemia 4% [1/25], thrombocytopenia 4.0% [1/25], and dermatologic 1.5% [2/131]). There were no significant differences among dogs with (n = 37) or without potential AEs (n = 94) in regards to sex, age, body weight, or dosage of MMF (P = .06, .13, .24, and .26, respectively). Conclusions and Clinical Importance In the dogs administered MMF, GI AEs were most common. Since potential hematologic and dermatologic AEs developed in a few dogs, clinicians should be aware of these when prescribing MMF to dogs with immune‐mediated disease.
Collapse
Affiliation(s)
- Kenjiro Fukushima
- Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Michael Lappin
- Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, USA
| | - Marie Legare
- Department of Environmental and Radiological Health Science, Colorado State University, Fort Collins, Colorado, USA
| | - Julia Veir
- Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, USA
| |
Collapse
|
|
10
|
Gota V, Purohit V, Gurjar M, Nayak L, Punatar S, Gokarn A, Bonda A, Bagal B, Vora CS, Patil A, Nookala M, Khattry N. A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation. Cell Transplant 2021; 29:963689720912925. [PMID: 32495641 PMCID: PMC7444217 DOI: 10.1177/0963689720912925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
A universally accepted strategy for therapeutic drug monitoring (TDM) of
mycophenolate mofetil (MMF) in the prevention of acute graft-versus-host disease
(aGVHD) in allogenic hematopoietic stem cell transplantation (alloHSCT) does not
exist. We explored the feasibility of developing a limited sampling strategy
(LSS) for TDM of MMF in this setting. Patients undergoing alloHSCT received
standard MMF-cyclosporine prophylaxis, with MMF administered twice daily (BD)
for matched transplant recipients or thrice daily (TID) in haploidentical
transplantation. Intensive blood sampling was carried out on day 7 and area
under the concentration–time curve (AUC) of mycophenolic acid (MPA), the active
metabolite, was estimated using noncompartmental analysis. The ability of MPA
exposure defined by AUC0-12 to discriminate between responders
(patients who did not develop GVHD) and nonresponders (patients who developed
GVHD) was determined by receiver operating characteristic curve analysis.
Patients were divided into training and validation sets within BD and TID
groups. Mathematical equations were developed from the training set to predict
AUC0-12 from an abbreviated AUC involving a limited number of
sampling points. The equations were validated in the validation set by comparing
the MPA AUC0-12 predicted from LSS with the observed
AUC0-12. It was observed that patients with AUC0-12
≤18.99 mg*h/L had a higher risk of developing aGVHD [odds ratio (OR) = 2.63
(1.17 to 5.87), P = 0.06]. The benefit was more in matched
transplant recipients [OR = 3.5 (1.30 to 9.49), P = 0.05] as
compared to haploindentical transplant [OR = 2.8 (0.49 to 15.91),
P = NS]. Using the mathematical equations, the observed
AUC0-12 was predicted with 92.31% accuracy in the BD subset and
100% accuracy in the TID subset for a combined accuracy of 94.76%. A set of just
three samples that constituted the abbreviated AUC1-4 was used to
develop the predictive models. The LSS could be employed for the therapeutic
monitoring of MMF particularly in patients undergoing matched hematopoietic stem
cell transplantation.
Collapse
Affiliation(s)
- Vikram Gota
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.,Homi Bhabha National Institute, Mumbai, Maharastra, India
| | - Vaitashi Purohit
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Murari Gurjar
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Lingaraj Nayak
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Sachin Punatar
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Anant Gokarn
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Avinash Bonda
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Bhausaheb Bagal
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Chakor Sunil Vora
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Anand Patil
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Manjunath Nookala
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| | - Navin Khattry
- Homi Bhabha National Institute, Mumbai, Maharastra, India.,Bone Marrow Transplant Unit, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India
| |
Collapse
|
|
11
|
Bergan S, Brunet M, Hesselink DA, Johnson-Davis KL, Kunicki PK, Lemaitre F, Marquet P, Molinaro M, Noceti O, Pattanaik S, Pawinski T, Seger C, Shipkova M, Swen JJ, van Gelder T, Venkataramanan R, Wieland E, Woillard JB, Zwart TC, Barten MJ, Budde K, Dieterlen MT, Elens L, Haufroid V, Masuda S, Millan O, Mizuno T, Moes DJAR, Oellerich M, Picard N, Salzmann L, Tönshoff B, van Schaik RHN, Vethe NT, Vinks AA, Wallemacq P, Åsberg A, Langman LJ. Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2021; 43:150-200. [PMID: 33711005 DOI: 10.1097/ftd.0000000000000871] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/29/2021] [Indexed: 12/13/2022]
Abstract
ABSTRACT When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.
Collapse
Affiliation(s)
- Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Kamisha L Johnson-Davis
- Department of Pathology, University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Paweł K Kunicki
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | - Florian Lemaitre
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France
| | - Pierre Marquet
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Mariadelfina Molinaro
- Clinical and Experimental Pharmacokinetics Lab, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Ofelia Noceti
- National Center for Liver Tansplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | | | - Tomasz Pawinski
- Department of Drug Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Warszawa, Poland
| | | | - Maria Shipkova
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jesse J Swen
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eberhard Wieland
- Synlab TDM Competence Center, Synlab MVZ Leinfelden-Echterdingen GmbH, Leinfelden-Echterdingen, Germany
| | - Jean-Baptiste Woillard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | - Tom C Zwart
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Markus J Barten
- Department of Cardiac- and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Maja-Theresa Dieterlen
- Department of Cardiac Surgery, Heart Center, HELIOS Clinic, University Hospital Leipzig, Leipzig, Germany
| | - Laure Elens
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics (PMGK) Research Group, Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institut de Recherche Expérimentale et Clinique, UCLouvain and Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Satohiro Masuda
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk J A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Nicolas Picard
- INSERM, Université de Limoges, Department of Pharmacology and Toxicology, CHU de Limoges, U1248 IPPRITT, Limoges, France
| | | | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital, Heidelberg, Germany
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Nils Tore Vethe
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Alexander A Vinks
- Department of Pharmacy, International University of Health and Welfare Narita Hospital, Chiba, Japan
| | - Pierre Wallemacq
- Clinical Chemistry Department, Cliniques Universitaires St Luc, Université Catholique de Louvain, LTAP, Brussels, Belgium
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet and Department of Pharmacy, University of Oslo, Oslo, Norway; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
12
|
Dungdung R, Bayal M, Valliyott L, Unniyampurath U, Nair SS, Pilankatta R. A slow, efficient and safe nanoplatform of tailored ZnS QD-mycophenolic acid conjugates for in vitro drug delivery against dengue virus 2 genome replication. NANOSCALE ADVANCES 2020; 2:5777-5789. [PMID: 36133864 PMCID: PMC9418522 DOI: 10.1039/d0na00725k] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 10/05/2020] [Indexed: 06/16/2023]
Abstract
Dengue is a major health concern causing significant mortality, morbidity and economic loss. The development of anti-dengue viral drugs is challenging due to high toxicity, as well as off-target/side effects. We engineered size tuned ZnS QDs as a platform for the efficient delivery of mycophenolic acid (MPA) against dengue virus serotype 2 (DENV2) to evaluate the drug efficacy and toxicity using the DENV2 sub-genomic replicon system in BHK21 cells. The results indicate that the Selectivity Index 50 (SI50) of the ZnS QD-MPA conjugate was two orders higher than that of free MPA with lower cytotoxicity. The effect is attributed to the sustained release of MPA from ZnS QD-MPA. The conjugated MPA caused significant inhibition of the virus at the level of replication and viral protein translation. The study underpins the efficiency of the ZnS QD for the delivery of antiviral drugs against DENV2 with negligible toxicity and side effects.
Collapse
Affiliation(s)
- Ranjeet Dungdung
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Krishna Block, Central University of Kerala Periya Kasargod Kerala India 671316
| | - Manikanta Bayal
- Department of Physics, School of Physical Sciences, Narmada Block, Central University of Kerala Periya Kasargod Kerala India 671316
| | - Lathika Valliyott
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Krishna Block, Central University of Kerala Periya Kasargod Kerala India 671316
| | | | - Swapna S Nair
- Department of Physics, School of Physical Sciences, Narmada Block, Central University of Kerala Periya Kasargod Kerala India 671316
| | - Rajendra Pilankatta
- Department of Biochemistry and Molecular Biology, School of Biological Sciences, Krishna Block, Central University of Kerala Periya Kasargod Kerala India 671316
| |
Collapse
|
|
13
|
Recalcitrant Esophageal Stricture Secondary to Mycophenolate Mofetil. Case Rep Gastrointest Med 2020; 2020:8817801. [PMID: 33299620 PMCID: PMC7704200 DOI: 10.1155/2020/8817801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 11/11/2020] [Indexed: 11/17/2022] Open
Abstract
Mycophenolate mofetil (MMF) is associated with various gastrointestinal toxicities. However, limited literature studies exist reporting MMF-related gastrointestinal toxicity manifesting as esophageal strictures. We report a case of a 62-year-old male with kidney transplant on MMF, tacrolimus, and prednisone, presenting with progressive dysphagia and odynophagia. Esophagogastroduodenoscopy revealed severe esophageal stricturing with near food bolus impaction, requiring dilations, esophageal stent, and ultimately gastrostomy tube. Biopsies revealed nonspecific inflammation with no evidence of infectious/neoplastic process; thus, our multidisciplinary esophageal group determined that the process was secondary to MMF. This case demonstrates that, though rare, MMF can result in severe esophageal strictures causing significant morbidity.
Collapse
|
|
14
|
Turshudzhyan A, Inyangetor D. Uremic and Post-Transplant Gastropathy in Patients With Chronic Kidney Disease and End-Stage Renal Disease. Cureus 2020; 12:e10578. [PMID: 32983742 PMCID: PMC7510509 DOI: 10.7759/cureus.10578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Gastrointestinal (GI) mucosal lesions are common in chronic kidney disease (CKD), end-stage renal disease (ESRD), and in post-renal transplant period. However, etiology of mucosal lesions pre- and post-transplant is very different. Gastropathy in non-transplant ESRD patients usually develops because of uremia, chronic anemia, and fluctuations in the gastric blood supply during hemodialysis, eventually leading to uremic gastritis. Gastropathy in post-transplant patients tends to be associated with immunosuppressive therapies. Helicobacter pylori infection is more prevalent in uremic patients than in post-transplant patients. Uremia can also lead to uremic arteriolopathy and autonomic nervous system dysfunction, which can present with GI symptoms mimicking uremic gastropathy. Post-transplantation immunosuppressive therapies have been linked to GI mucosal lesions as well. These lesions carry a poor prognostic factor disrupting the function of the GI tract, which in turn affects the pharmacokinetics of the immunosuppressive drugs eventually leading to poor graft survival and increased mortality. Mycophenolate mofetil is one of the agents more associated with intestinal erosions. Recognizing uremic gastropathy and intervening early helps prevent post-transplant GI complications. Acid controlling therapies can be an effective prophylaxis against both gastropathies. Using enteric-coated formulation for immunosuppressive agents may slow down the mucosal insult. Treatment of H. pylori in both patient populations may help prevent further mucosal injury. Lastly, timely screening for symptoms may help start treatment early and prevent progression to serious gastropathy.
Collapse
|
|
15
|
Abstract
Mycophenolate Mofetil (MMF) is routinely used immunosuppressant in solid organ transplantation is commonly associated with several gastrointestinal (GI) side effects. Here we present a case of giant gastric ulcer of 5 cm from MMF use post cardiac transplant. CASE DESCRIPTION: A 56-year-old male with history of severe ischemic cardiomyopathy post heart transplant was on immunosuppression with MMF, tacrolimus and prednisone for 5 months. He presented with severe epigastric pain and intermittent episodes of melena for 1 month. His pain radiated to back that is worsened with eating. Associated with loss of appetite, vomiting and 16-pound weight loss in 3 months. He never smoked, drank alcohol or used over the counter pain medications. He was profoundly anemic requiring blood transfusions. EGD performed demonstrated very large clean-based ulcer of 5 cm diameter in the body, smaller ulcer of 8 mm diameter in pre-pyloric region and 5-10 small aphthous ulcers in the gastric body and fundus. Gastric biopsies taken from the ulcer were negative for Helicobacter pylori, cytomegalovirus and malignancy. Flexible sigmoidoscopy revealed non-bleeding inflamed internal hemorrhoids. Consequently, MMF was discontinued and switched to azathioprine. He was treated with twice daily proton pump inhibitor therapy with resolution of abdominal pain, improved appetite and weight gain. DISCUSSION: MMF is well known for common GI side-effects such as nausea, diarrhea, vomiting, ulcers, abdominal pain and rarely gastrointestinal bleeding. Few studies reported 3 to 8% incidence of ulcer perforation and GI bleeding within 6 months. Risk of gastroduodenal erosions is nearly 1.83 times for MMF, with the highest lesions associated with MMF-tacrolimus-corticosteroid combination treatment as seen in our patient. Hypothesis is that GI tract is vulnerable because of dependence of enterocytes on de novo synthesis of purines, which is disrupted by MMF. Typically, upper GI mucosal injuries of mucosal irritation leading to esophagitis, gastritis and/or ulcers are seen. Endoscopy is both diagnostic and therapeutic if bleeding gastric ulcers are noted. Minor complications improve with reduction of drug dose or use of enteric coated preparation if feasible. Discontinuation of the drug is main stay in the management of MMF related ulcer disease. Simple medical treatment with either H2-receptor antagonists, proton-pump inhibitors, coating agents, prostaglandins or combination has proven effective in most cases. Considering excellent results with medical management of ulcer, role of surgery is limited.
Collapse
Affiliation(s)
- Aamer Abbass
- Division of Gastroenterology and Hepatology, University of New Mexico, MSC 10-5550, Albuquerque, NM, 87131, USA.
| | - Sameen Khalid
- Division of Gastroenterology and Hepatology, University of New Mexico, MSC 10-5550, Albuquerque, NM, 87131, USA
| | - Vaishnavi Boppana
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Joshua Hanson
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Henry Lin
- Division of Gastroenterology and Hepatology, University of New Mexico, MSC 10-5550, Albuquerque, NM, 87131, USA
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Denis McCarthy
- Division of Gastroenterology and Hepatology, University of New Mexico, MSC 10-5550, Albuquerque, NM, 87131, USA
| |
Collapse
|
|
16
|
Metz DK, Holford N, Kausman JY, Walker A, Cranswick N, Staatz CE, Barraclough KA, Ierino F. Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention. Transplantation 2019; 103:2012-2030. [PMID: 31584924 PMCID: PMC6756255 DOI: 10.1097/tp.0000000000002762] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/29/2019] [Accepted: 04/03/2019] [Indexed: 12/24/2022]
Abstract
The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise "one-dose-fits-all" approach should be replaced by the clinically proven MPA target concentration strategy.
Collapse
Affiliation(s)
- David K. Metz
- Department of Nephrology, Royal Children’s Hospital, Melbourne, VIC, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children’s Research Institute, Melbourne, VIC, Australia
- Clinical Pharmacology Unit, Royal Children’s Hospital, Melbourne, VIC, Australia
| | - Nick Holford
- Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand
| | - Joshua Y. Kausman
- Department of Nephrology, Royal Children’s Hospital, Melbourne, VIC, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children’s Research Institute, Melbourne, VIC, Australia
| | - Amanda Walker
- Department of Nephrology, Royal Children’s Hospital, Melbourne, VIC, Australia
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children’s Research Institute, Melbourne, VIC, Australia
| | - Noel Cranswick
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Murdoch Children’s Research Institute, Melbourne, VIC, Australia
- Clinical Pharmacology Unit, Royal Children’s Hospital, Melbourne, VIC, Australia
| | | | - Katherine A. Barraclough
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Department of Nephrology, Royal Melbourne Hospital, Melbourne, VIC, Australia
| | - Francesco Ierino
- Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia
- Department of Nephrology, St Vincent’s Health, Melbourne, VIC, Australia
| |
Collapse
|
|
17
|
Meaney CJ, Sudchada P, Consiglio JD, Wilding GE, Cooper LM, Venuto RC, Tornatore KM. Influence of Calcineurin Inhibitor and Sex on Mycophenolic Acid Pharmacokinetics and Adverse Effects Post-Renal Transplant. J Clin Pharmacol 2019; 59:1351-1365. [PMID: 31062373 PMCID: PMC7375007 DOI: 10.1002/jcph.1428] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 04/05/2019] [Indexed: 12/15/2022]
Abstract
Tacrolimus or cyclosporine is prescribed with mycophenolic acid posttransplant and contributes to interpatient variability in mycophenolic acid pharmacokinetics and response. Cyclosporine inhibits enterohepatic circulation of the metabolite mycophenolic acid glucuronide, which is not described with tacrolimus. This study investigated mycophenolic acid pharmacokinetics and adverse effects in stable renal transplant recipients and the association with calcineurin inhibitors, sex, and race. Mycophenolic acid and mycophenolic acid glucuronide area under the concentration-time curve from 0 to 12 hours (AUC0-12h ) and apparent clearance were determined at steady state in 80 patients receiving cyclosporine with mycophenolate mofetil and 67 patients receiving tacrolimus with mycophenolate sodium. Gastrointestinal adverse effects and hematologic parameters were evaluated. Statistical models evaluated mycophenolic acid pharmacokinetics and adverse effects. Mycophenolic acid AUC0-12h was 1.70-fold greater with tacrolimus (68.9 ± 30.9 mg·h/L) relative to cyclosporine (40.8 ± 17.6 mg·h/L); P < .001. Target mycophenolic acid AUC0-12h of 30-60 mg·h/L was achieved in 56.3% on cyclosporine compared with 34.3% receiving tacrolimus (P < .001). Mycophenolic acid clearance was 48% slower with tacrolimus (10.6 ± 4.7 L/h) relative to cyclosporine (20.5 ± 10.0 L/h); P < .001. Enterohepatic circulation occurred less frequently with cyclosporine (45%) compared with tacrolimus (78%); P < 0.001; with a 2.9-fold greater mycophenolic acid glucuronide AUC0-12h to mycophenolic acid AUC0-12h ratio (P < .001). Race did not affect mycophenolic acid pharmacokinetics. Gastrointestinal adverse effect scores were 2.2-fold higher with tacrolimus (P < .001) and more prominent in women (P = .017). Lymphopenia was more prevalent with tacrolimus (52.2%) than cyclosporine (22.5%); P < 0.001. Calcineurin inhibitors and sex contributed to interpatient variability in mycophenolic acid pharmacokinetics and adverse effects post-renal transplant, which could be attributed to differences in enterohepatic circulation.
Collapse
Affiliation(s)
- Calvin J. Meaney
- Immunosuppressive Pharmacology Research Program,
Translational Pharmacology Research Core, Buffalo, NY, USA
- Department of Pharmacy Practice, School of Pharmacy and
Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Patcharaporn Sudchada
- Immunosuppressive Pharmacology Research Program,
Translational Pharmacology Research Core, Buffalo, NY, USA
| | - Joseph D. Consiglio
- Department of Biostatistics, School of Public Health and
Health Professions, University at Buffalo, Buffalo, NY, USA
| | - Gregory E. Wilding
- Department of Biostatistics, School of Public Health and
Health Professions, University at Buffalo, Buffalo, NY, USA
| | - Louise M. Cooper
- Immunosuppressive Pharmacology Research Program,
Translational Pharmacology Research Core, Buffalo, NY, USA
- Department of Pharmacy Practice, School of Pharmacy and
Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Rocco C. Venuto
- Department of Medicine; Nephrology Division, Jacobs School
of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Kathleen M. Tornatore
- Immunosuppressive Pharmacology Research Program,
Translational Pharmacology Research Core, Buffalo, NY, USA
- Department of Pharmacy Practice, School of Pharmacy and
Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
- Department of Medicine; Nephrology Division, Jacobs School
of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| |
Collapse
|
|
18
|
Dridi I, Chaabane A, Ben-Cherif W, Aouam K, Haouas Z, Ben-Attia M, Boughattas NA. Circadian variation in intestine toxicity of Mycophenolate mofetil in rats: an experimental and histopathologic study. BIOL RHYTHM RES 2018. [DOI: 10.1080/09291016.2018.1533732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Ichrak Dridi
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Amel Chaabane
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Wafa Ben-Cherif
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Karim Aouam
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Zohra Haouas
- Laboratory of Histology Embryology and Cytogenetic, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| | - Mossadok Ben-Attia
- Laboratory of Biomonitoring of the Environment, Faculty of Sciences of Bizerte, Carthage University, Zarzouna, Tunisia
| | - Naceur A. Boughattas
- Laboratory of Pharmacology, Faculty of Medicine, University of Monastir, Monastir, Tunisia
| |
Collapse
|
|
19
|
Klotsman M, Sathyan G, Anderson WH, Garden OA, Shivanand P. Mycophenolic acid in patients with immune-mediated inflammatory diseases: From humans to dogs. J Vet Pharmacol Ther 2018; 42:127-138. [PMID: 30375004 DOI: 10.1111/jvp.12731] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/02/2018] [Accepted: 10/03/2018] [Indexed: 12/26/2022]
Abstract
Mycophenolic acid (MPA), a noncompetitive, selective and reversible inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), is an immunosuppressive agent that has a long history in medicine. Mechanistically, the inhibition of IMPDH leads to the selective and eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil (MMF), the first MPA-based product to receive marketing approval over two decades ago, was originally indicated for the prophylaxis of organ rejection in human transplant patients. Given its broad immunosuppressive properties and ability to selectively inhibit lymphocyte division and effector functions, the clinical utility of MPA was subsequently explored in a host of autoimmune diseases. Human clinical studies have shown MPA to be safe and effective and support its off-label administration for immune-mediated diseases such as lupus, myasthenia gravis and atopic dermatitis. MMF became generically available in the United States in 2008, and its clinical utility is increasingly being explored as a treatment option for dogs with immune-mediated diseases. This review summarizes the available literature for MPA pharmacokinetics and pharmacodynamics, and the current status of MPA as a treatment for client-owned dogs diagnosed with immune-mediated diseases.
Collapse
Affiliation(s)
| | | | - Wayne H Anderson
- Okava Pharmaceuticals, San Francisco, California.,Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Oliver A Garden
- Clinical Sciences & Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
| | | |
Collapse
|
|
20
|
Celiac-like Enteropathy Associated With Mycophenolate Sodium in Renal Transplant Recipients. Transplant Direct 2018; 4:e375. [PMID: 30255135 PMCID: PMC6092177 DOI: 10.1097/txd.0000000000000812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 05/24/2018] [Accepted: 05/30/2018] [Indexed: 01/19/2023] Open
Abstract
Background Although colonic injury is a well-known complication of mycophenolic acid (MPA), the involvement of the upper gastrointestinal tract is less extensively documented. We present the occurrence of celiac-like duodenopathy manifested as a severe diarrhea syndrome in 2 renal transplant recipients on enteric-coated mycophenolate sodium. Methods The patients belong to a setting of 16 renal transplant recipients under MPA suffering from chronic diarrhea in the absence of MPA-related colitis. Results Both patients had a history of persistent diarrhea with significant weight loss. Colonic mucosa was unremarkable, whereas duodenal biopsies revealed celiac-like changes with increased epithelial cell apoptosis. Clinical symptoms completely resolved, and follow-up biopsies demonstrated normalization of histology after enteric-coated mycophenolate sodium withdrawal and switching to azathioprine. Conclusions Celiac-like enteropathy seems to represent a rare side effect of MPA-associated immunosuppressive therapy and should be taken into account in the differential diagnosis of diarrhea in transplant recipients treated with MPA particularly in the absence of MPA-related colitis. As macroscopic lesions are usually missing, blind duodenal biopsies are necessary to establish the diagnosis.
Collapse
|
|
21
|
Lancia P, Aurich B, Ha P, Maisin A, Baudouin V, Jacqz-Aigrain E. Adverse Events under Tacrolimus and Cyclosporine in the First 3 Years Post-Renal Transplantation in Children. Clin Drug Investig 2018; 38:157-171. [PMID: 29236209 DOI: 10.1007/s40261-017-0594-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3 years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics. METHODS This retrospective study included all children who underwent a renal transplant at Hospital Robert Debré between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4. RESULTS One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p < 0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p < 0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (> 20%) and cyclosporine (> 10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics. CONCLUSIONS The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation.
Collapse
Affiliation(s)
- Pauline Lancia
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Beate Aurich
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Phuong Ha
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Anne Maisin
- Department of Paediatric Nephrology, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Véronique Baudouin
- Department of Paediatric Nephrology, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Evelyne Jacqz-Aigrain
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France. .,Clinical Investigation Center CIC1426, INSERM, Paris, France. .,Paris Diderot University, Sorbonne Paris Cité, Paris, France.
| |
Collapse
|
|
22
|
Feturi FG, Weinstock M, Zhao W, Zhang W, Schnider JT, Erbas VE, Oksuz S, Plock JA, Rohan L, Spiess AM, Ferreira LM, Solari MG, Venkataramanan R, Gorantla VS. Mycophenolic Acid for Topical Immunosuppression in Vascularized Composite Allotransplantation: Optimizing Formulation and Preliminary Evaluation of Bioavailability and Pharmacokinetics. Front Surg 2018; 5:20. [PMID: 29868602 PMCID: PMC5954844 DOI: 10.3389/fsurg.2018.00020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 02/19/2018] [Indexed: 12/21/2022] Open
Abstract
Mycophenolic acid (MPA), is the active form of the ester prodrug mycophenolate mofetil (MMF). MMF is an FDA approved immunosuppressive drug that has been successfully used in systemic therapy in combination with other agents for the prevention of acute rejection (AR) following solid organ transplantation (SOT) as well as in vascularized composite allotransplantation (VCA). Systemic use of MMF is associated with gastrointestinal adverse effects. Topical delivery of the prodrug could thus provide graft-targeted immunosuppression while minimizing systemic drug exposure. Our goal was to develop a topical formulation of MPA with optimal in vitro/in vivo characteristics such as release, permeation, and tissue bioavailability to enable safety and efficacy evaluation in clinical VCA. Permeation studies were performed with a solution of MPA (10 mg/ml). In vitro release and permeation studies were performed for different semisolid formulations (Aladerm, Lipoderm, emollient, and VersaBase) of MPA (1% w/w) using a Franz Diffusion Cell System (FDCS). In vivo pharmacokinetic characterization of MPA release from Lipoderm was performed in rats. MPA in solution exhibited a steady state flux (3.8 ± 0.1 µg/cm2/h) and permeability (1.1 × 10−7 ± 3.2 × 10−9 cm/s). MPA in Lipoderm exhibited a steady state flux of 1.12 ± 0.24 µg/cm2/h, and permeability of 6.2 × 10−09 ± 1.3 × 10−9 cm/s across the biomimetic membrane. The cumulative release of MPA from Lipoderm, showed a linear single-phase profile with a R2 of 0.969. In vivo studies with MPA in Lipoderm showed markedly higher local tissue MPA levels and lower systemic MPA exposure as compared to values obtained after intravenous delivery of the same dose of drug (p < 0.05). We successfully developed for the first time, a topical formulation of MPA in Lipoderm with optimal in vitro/in vivo permeability characteristics and no undesirable local or systemic adverse effects in vivo. Our study provides key preliminary groundwork for translational efficacy studies of topical MPA in pre-clinical large animal VCA models and for effectiveness evaluation in patients receiving VCA.
Collapse
Affiliation(s)
- Firuz G Feturi
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
| | - Matthias Weinstock
- Disciplina de Cirurgia Plástica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Wenchen Zhao
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
| | - Wei Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.,Magee-Womens Research Institute, Pittsburgh, PA, United States
| | - Jonas T Schnider
- Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Vasil E Erbas
- Department of Plastic Surgery, Medicalpark Gaziantep Hastanesi, Gaziantep, Turkey
| | - Sinan Oksuz
- Department of Plastic Reconstructive and Aesthetic Surgery, Gulhane Medical School, Ankara, Turkey
| | - Jan A Plock
- Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Lisa Rohan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.,Magee-Womens Research Institute, Pittsburgh, PA, United States
| | - Alexander M Spiess
- Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Lydia M Ferreira
- Disciplina de Cirurgia Plástica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Mario G Solari
- Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.,McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States
| | - Vijay S Gorantla
- Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.,McGowan Institute for Regenerative Medicine, Pittsburgh, PA, United States.,Wake Forest Institute for Regenerative Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States
| |
Collapse
|
|
23
|
Grobman M, Boothe DM, Rindt H, Williamson BG, Katz ML, Coates JR, Reinero CR. Pharmacokinetics and dynamics of mycophenolate mofetil after single-dose oral administration in juvenile dachshunds. J Vet Pharmacol Ther 2017. [PMID: 28649788 DOI: 10.1111/jvp.12420] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young-aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose-bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole-blood mitogen-stimulated T-cell proliferation was determined using a flow cytometric assay. Plasma MPA Cmax (mean ± SD, 9.33 ± 7.04 μg/ml) occurred at <1 hr. The AUC0-∞ (mean ± SD, 12.84±6.62 hr*μg/ml), MRTinf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.
Collapse
Affiliation(s)
- M Grobman
- Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - D M Boothe
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine Auburn University, Auburn, AL, USA
| | - H Rindt
- Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - B G Williamson
- Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - M L Katz
- Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA
| | - J R Coates
- Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - C R Reinero
- Department of Veterinary Medicine and Surgery, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| |
Collapse
|
|
24
|
Heischmann S, Christians U. Validation of the cell line LS180 as a model for study of the gastrointestinal toxicity of mycophenolic acid. Xenobiotica 2017; 48:433-441. [DOI: 10.1080/00498254.2017.1329567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Svenja Heischmann
- iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado Denver, Aurora, CO, USA and
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Uwe Christians
- iC42 Clinical Research and Development, Department of Anesthesiology, School of Medicine, University of Colorado Denver, Aurora, CO, USA and
| |
Collapse
|
|
25
|
The Immunosuppressant Mycophenolic Acid Alters Nucleotide and Lipid Metabolism in an Intestinal Cell Model. Sci Rep 2017; 7:45088. [PMID: 28327659 PMCID: PMC5361167 DOI: 10.1038/srep45088] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 02/16/2017] [Indexed: 01/14/2023] Open
Abstract
The study objective was to elucidate the molecular mechanisms underlying the negative effects of mycophenolic acid (MPA) on human intestinal cells. Effects of MPA exposure and guanosine supplementation on nucleotide concentrations in LS180 cells were assessed using liquid chromatography-mass spectrometry. Proteomics analysis was carried out using stable isotope labeling by amino acids in cell culture combined with gel-based liquid chromatography-mass spectrometry and lipidome analysis using 1H nuclear magnetic resonance spectroscopy. Despite supplementation, depletion of guanosine nucleotides (p < 0.001 at 24 and 72 h; 5, 100, and 250 μM MPA) and upregulation of uridine and cytidine nucleotides (p < 0.001 at 24 h; 5 μM MPA) occurred after exposure to MPA. MPA significantly altered 35 proteins mainly related to nucleotide-dependent processes and lipid metabolism. Cross-reference with previous studies of MPA-associated protein changes widely corroborated these results, but showed differences that may be model- and/or method-dependent. MPA exposure increased intracellular concentrations of fatty acids, cholesterol, and phosphatidylcholine (p < 0.01 at 72 h; 100 μM MPA) which corresponded to the changes in lipid-metabolizing proteins. MPA affected intracellular nucleotide levels, nucleotide-dependent processes, expression of structural proteins, fatty acid and lipid metabolism in LS180 cells. These changes may compromise intestinal membrane integrity and contribute to gastrointestinal toxicity.
Collapse
|
|
26
|
Pharmacokinetics of Mycophenolic Acid and Dose Optimization in Children After Intestinal Transplantation. Ther Drug Monit 2016; 39:37-42. [PMID: 27898598 DOI: 10.1097/ftd.0000000000000363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (MPS) is now commonly used in pediatric intestinal transplantation (Tx), but to date, no clear recommendations regarding the dosing regimen have been made in this population. The aim of this study was to determine the MMF/MPS dosage required to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) for mycophenolic acid (MPA) greater than 30 mg·h·L in children after intestinal transplantation. METHODS A pharmacokinetic study was conducted in 8 children (median, 9.4 years; range, 0.75-15.8 years) at a median time of 113 months (range, 1.5-160 months) after intestinal transplantation. RESULTS MMF was initially introduced at a low median starting dose of 687 mg·m·d (range, 310-1414 mg·m·d). One of the 3 patients who received MPS and 2 of the 6 patients who received MMF had an MPA AUC0-12 value below 30 mg.h.L. The median MMF dosage had to be increased by 91% (1319 mg·m·d versus 687 mg·m·d) to reach AUC0-12 values above the defined target level of 30 mg·h·L. CONCLUSIONS When used in combination with tacrolimus and steroids, an initial MMF dose of 600 mg/m twice a day would be recommended to children after intestinal transplantation to achieve MPA exposure similar to those observed in adults and children after the transplantation of other organs. Further studies are required to recommend a suitable dosage for pediatric intestinal transplant recipients who receive MPA.
Collapse
|
|
27
|
Królikowski J, Pawłowicz E, Budzisz E, Nowicki M. Effect of the Prophylactic Use of Proton-Pump Inhibitors on the Pattern of Gastrointestinal Symptoms in Patients Late After Kidney Transplant. EXP CLIN TRANSPLANT 2016; 14:503-510. [PMID: 27212101 DOI: 10.6002/ect.2015.0252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Although immunosuppressive drugs have been recognized as leading causes of gastrointestinal symptoms after kidney transplant, other widely used medications such as proton-pump inhibitors recently have been implicated. Our aim was to study the effects of chronic proton-pump inhibitor therapy on gastrointestinal symptoms in clinically stable patients late after kidney transplant. MATERIALS AND METHODS The study comprised 100 kidney transplant recipients (66 men and 34 women, mean age of 49 ± 12 y, mean time after transplant of 56 ± 46 mo). All patients completed the Gastrointestinal Symptoms Rating Scale and the Quality of Life Questionnaire SF-8 surveys. RESULTS The most commonly reported symptoms included borborygmus (27%), flatulence (23%), abdominal distension (18%), urgent need of defecation (17%), and heartburn, acid reflux, and eructation (13%). Proton-pump inhibitors were chronically used by 50% of patients and sporadically by 33%. Gastrointestinal Symptoms Rating Scale scores were higher in patients who used proton-pump inhibitors (mean score of 7.8 ± 5.5 vs 4.6 ± 3.0; P = .013). Total score of items representing diarrhea in the Gastrointestinal Symptoms Rating Scale (increased passage of stools, loose stools, urgent need of defecation, incomplete evacuation) was higher in patients treated with proton-pump inhibitors than in those not treated (2.3 ± 2.2 vs 1.3 ± 1.9; P = .04). CONCLUSIONS Chronic use of proton-pump inhibitors may increase the prevalence of gastrointestinal symptoms, particularly diarrhea, in patients late after kidney transplant.
Collapse
Affiliation(s)
- Jerzy Królikowski
- From the Department of Nephrology, Hypertension and Kidney Transplantation, Medical University of Lodz, Lodz, Poland
| | | | | | | |
Collapse
|
|
28
|
Karbelkar SA, Majumdar AS. Altered systemic bioavailability and organ distribution of azathioprine in methotrexate-induced intestinal mucositis in rats. Indian J Pharmacol 2016; 48:241-7. [PMID: 27298491 PMCID: PMC4899994 DOI: 10.4103/0253-7613.182895] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2016] [Revised: 03/22/2016] [Accepted: 04/27/2016] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Intestinal mucositis is a significant problem haunting clinicians for decades. One of the major reasons for its occurrence is high-dose chemotherapy. The study is aimed at investigating effect of intestinal mucositis on pharmacokinetics, organ distribution, and bioavailability of azathioprine (AZA) (6-mercaptopurine). MATERIALS AND METHODS Intestinal mucositis was induced with methotrexate (MTX) (2.5 mg/kg). The oral absorption of AZA and 6-mercaptopurine (metabolite) levels were determined in control and MTX-treated rats: ex vivo (noneverted sac technique) and in vivo (pharmacokinetics and organ-distribution) using high-performance liquid chromatography. Immunohistochemistry was conducted to evaluate peptide transporter expression on luminal membrane of small intestine. RESULTS Intestinal permeation of AZA into systemic circulation of rats was lower after MTX administration, widely found in intestinal segments of mucositis-induced rats leading to decline in systemic bioavailability of AZA. Immunohistochemistry findings indicated diminution of peptide transporter expression representing hampered absorption of drugs absorbed via this transporter. CONCLUSION Study outcome has thrown light on altered fate of AZA when administered to individuals with mucositis which suggests modified drug therapy. These findings can further be investigated in different drug classes which might be administered concomitantly in mucositis and study outcome can be further confirmed in mucositis patients in clinical practice also.
Collapse
Affiliation(s)
- Sadaf A. Karbelkar
- Department of Pharmacology, Bombay College of Pharmacy, Mumbai, Maharashtra, India
| | - Anuradha S. Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Mumbai, Maharashtra, India
| |
Collapse
|
|
29
|
Abstract
The adverse effects of mycophenolate mofetil on the colon are well known. However, isolated small intestinal involvement resulting in diarrhea and severe weight loss is infrequently reported in the literature. We present the case of a 45-year-old woman on mycophenolate mofetil following renal transplant, who presented with abdominal pain and weight loss. An esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A small bowel capsule study revealed extensive enteropathy of jejunum and ileum that was confirmed on a push enteroscopy with biopsies. Her symptoms completely resolved after being switched to enteric-coated mycophenolic acid.
Collapse
|
|
30
|
Liu H, Wang Y, Fan B, Ren L, Wang W, Hu P, Zhang X. Improvement in Severe Mycophenolic Acid-associated Gastrointestinal Symptoms after Changing Enteric-coated Mycophenolate Sodium to Mizoribine in Renal Transplant Recipients: Two Case Reports. Intern Med 2016; 55:2005-10. [PMID: 27477406 DOI: 10.2169/internalmedicine.55.5968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Clinical results point to a better gastrointestinal tolerability with enteric-coated mycophenolate sodium as compared to mycophenolate mofetil. However, some transplant recipients who are treated with enteric-coated mycophenolate sodium still experience gastrointestinal symptoms. We herein present two cases of renal transplant recipients with severe gastrointestinal symptoms who were switched from enteric-coated mycophenolate sodium to mizoribine, and the symptom reversal effects were evaluated using the Gastrointestinal Symptom Rating Scale. The results of this study showed a significant improvement in severe gastrointestinal symptoms in renal transplant recipients after converting from enteric-coated mycophenolate sodium to mizoribine.
Collapse
Affiliation(s)
- Hang Liu
- Department of Urology, Chao Yang Hospital, China
| | | | | | | | | | | | | |
Collapse
|
|
31
|
Tornatore KM, Meaney CJ, Wilding GE, Chang SS, Gundroo A, Cooper LM, Gray V, Shin K, Fetterly GJ, Prey J, Clark K, Venuto RC. Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients. Clin Pharmacokinet 2015; 54:423-34. [PMID: 25511793 DOI: 10.1007/s40262-014-0213-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.
Collapse
Affiliation(s)
- Kathleen M Tornatore
- Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Immunosuppressive Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, 701 Ellicott Street, Buffalo, NY, 14203, USA,
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Abstract
BACKGROUND Gastrointestinal disorders (GDs) are common in renal transplant recipients. The main cause of GDs seems to be the use of immunosuppressive medications, especially mycophenolic acid in the form of mycophenolate mofetil (MMF). OBJECTIVE The aim of this study was to estimate the frequency and severity of GDs in renal allograft recipients with the use of the Gastrointestinal Symptom Rating Scale (GSRS). METHODS Eighty-five renal allograft recipients, 50 ± 12 years old, treated with methylprednisolone, calcineurin inhibitor (cyclosporine [CsA], n = 42; tacrolimus (TAC), n = 43), and MMF were studied. RESULTS At the time of completion of the GSRS questionnaire, 38 of the 85 patients (45%) already had their MMF dose reduced because of GDs. Only 15 patients (18%) were totally free from GDs. The most frequent and severe GDs recorded were indigestion and diarrhea who were significantly more frequent in women (P = .045). GDs were recorded in patients receiving both standard and reduced dose of MMF. MMF dose was significantly associated only with diarrhea. Although TAC-treated patients had the highest mean GSRS scores, no statistically significant differences were observed compared with CsA-treated patients. In 31 patients, MMF was replaced by enteric-coated mycophenolate sodium (EC-MPS) and new questionnaires were completed 1 month later. Significant improvement in total and all subscores of GSRS was demonstrated (P < .001). Although EC-MPS dose tolerated by the patients was higher than MMF dose, the difference was not statistically significant. CONCLUSIONS Female sex and the use of MMF, especially in combination with TAC, are related to the occurrence of severe gastrointestinal symptoms. Substitution of MMF with EC-MPS significantly reduces the severity of symptoms and permits the use of higher doses.
Collapse
|
|
33
|
Veličković-Radovanović RM, Janković SM, Milovanović JR, Catić-Đorđević AK, Spasić AA, Stefanović NZ, Džodić PL, Šmelcerović AA, Cvetković TP. Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach. Ren Fail 2015; 37:652-658. [PMID: 25707517 DOI: 10.3109/0886022x.2015.1010442] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The aim of this study was to develop a population pharmacokinetic (PK) model for clearance of mycophenolic acid (MPA) in adult renal transplant recipients, to quantify the PK parameters and the influence of covariates on the MPA pharmacokinetic parameters. Parameters associated with plasma concentrations of MPA at steady-state were analyzed in 70 renal transplant recipients (mean age 42.97 years; mean total body weight 75.33 kg) using nonlinear mixed-effect modeling (NONMEM). Characteristics of patients screened for influence on the pharmacokinetic parameters were gender, age, body weight, time after transplantation, whether the patient was diagnosed as having diabetes mellitus, organ source (living or deceased donor), biochemical parameters and co-therapy (tacrolimus, cyclosporine, prednisolone, omeprazole, bisoprolol, carvedilol, nifedipine). A validation set of 25 renal transplant recipients was used to estimate the predictive performance of population pharmacokinetic model. Typical mean value of MPA oral clearance, estimated by base model (without covariates) was 0.741 L h(-1). During population modeling, the full model showed that clearance of the MPA was significantly influenced by age, total daily dose of MPA, creatinine clearance, albumin level, status and gender of a donor, and the nifedipine and tacrolimus co-therapy. In the final model, clearance of MPA was reported to be significantly influenced by age, total daily dose of MPA and thenifedipine co-therapy. The derived model describes adequately MPA clearance in terms of characteristics of our patients, offering basis for individual pharmacotherapy approach.
Collapse
|
|
34
|
Chen H, Chen B. Clinical mycophenolic acid monitoring in liver transplant recipients. World J Gastroenterol 2014; 20:10715-10728. [PMID: 25152575 PMCID: PMC4138452 DOI: 10.3748/wjg.v20.i31.10715] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 06/03/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
In liver transplantation, the efficacy of mycophenolate mofetil (MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid (MPA) has not been fully accepted in liver transplantation as no long-term prospective study of concentration controlled vs fixed-dose prescribing of MMF has been done. This review addressed MPA measurement, pharmacokinetic variability and reasons of this variation, exposure related to acute rejection and MMF-associated side effects in liver transplant recipients. Limited sampling strategies to predict MPA area under the concentration-time curve have also been described, and the value of clinical use needs to be investigated in future. The published data suggested that a fixed-dosage MMF regimen might not be suitable and monitoring of MPA exposure seems helpful in various clinical settings of liver transplantation.
Collapse
|
|
35
|
Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update. Arch Toxicol 2014; 88:1351-89. [PMID: 24792322 DOI: 10.1007/s00204-014-1247-1] [Citation(s) in RCA: 145] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 04/15/2014] [Indexed: 12/22/2022]
Abstract
This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.
Collapse
|
|
36
|
Maneiro JR, Lopez-Canoa N, Salgado E, Gomez-Reino JJ. Maintenance therapy of lupus nephritis with mycophenolate or azathioprine: systematic review and meta-analysis. Rheumatology (Oxford) 2013; 53:834-8. [PMID: 24369416 DOI: 10.1093/rheumatology/ket429] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE The objective of this study was to summarize the comparative efficacy and safety of MMF and AZA as maintenance therapy for LN. METHODS Systematic review and meta-analysis of randomized clinical trials of MMF and AZA as maintenance therapy for LN were performed based on a sensitive search. Meta-regression was used to explore causes of heterogeneity. Safety was explored using crude and combined incidence rate ratios (IRRs) of the more frequent adverse events (AEs). RESULTS The search produced 7341 hits. Four randomized clinical trials and one long-term study were selected for detailed analysis. No significant differences between MMF and AZA were found in sustained remission, relapse, renal failure, creatinine increase or death. However, there was high heterogeneity in the design of studies, drug doses and treatment in the previous induction phase. Significant lower rates of discontinuation due to AEs occurred in the MMF group, with a relative risk (RR) of 0.60 (95% CI 0.41, 0.88) but significant risk of publication bias (Egger test, P = 0.012). Gastrointestinal manifestations were more common [combined IRR 1.68 (95% CI 1.06, 2.68)] and leucopoenia less frequent in the MMF group [combined IRR 0.14 (95% CI 0.05, 0.42)]. CONCLUSION The available data does not support the superiority of MMF or AZA as maintenance therapy for LN. Nevertheless, the high heterogeneity of studies included in the analysis makes this contention questionable.
Collapse
Affiliation(s)
- Jose R Maneiro
- Rheumatology Department, Complejo Hospitalario Universitario de Santiago de Compostela, c/ Travesía da Choupana s/n, 15701 Santiago de Compostela, Spain.
| | | | | | | |
Collapse
|
|
37
|
Liapis G, Boletis J, Skalioti C, Bamias G, Tsimaratou K, Patsouris E, Delladetsima I. Histological spectrum of mycophenolate mofetil-related colitis: association with apoptosis. Histopathology 2013; 63:649-658. [PMID: 24025088 DOI: 10.1111/his.12222] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 07/01/2013] [Indexed: 12/26/2022]
Abstract
AIMS The main purpose of this study was to define diagnostic histological characteristics of mycophenolate mofetil (MMF)-related colitis in association with crypt epithelial cell turnover. METHODS AND RESULTS The examined material included 43 colonic biopsies from renal transplant recipients with MMF administration and persistent diarrhoea. Thirty-three cases showed MMF-related colitis, while 10 showed no significant changes. The histological findings were scored and correlated with the apoptotic index (AI) and with the proliferation rate (PR) of the crypt epithelium examined by TUNEL assay and Ki-67 immunoexpression. Ten cases of Crohn disease and 10 of ulcerative colitis were used as comparative groups. Crypt distortion and loss as well as increased apoptosis constituted the main features, their degree and combination leading either to an inflammatory bowel disease (IBD)-like (82%) or to a graft-versus-host disease-like pattern (18%). A high AI was associated more frequently with moderate and severe crypt distortion, while the values were significantly higher compared with the control groups (P < 0.01). High PR was noted in 18 of 29 (62.1%) of the cases. CONCLUSIONS The diagnostic hallmark of MMF-related colitis is an IBD-like histological pattern in association with increased epithelial apoptosis, while apoptotic cell death seems to be a potential pathogenetic factor of mucosa injury.
Collapse
Affiliation(s)
- George Liapis
- 1st Department of Pathology Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Costa ALDO, Enéas PCR, Miranda TA, Mingoti SA, Soares CDV, Pianetti GA. In vitro dissolution kinetic for mycophenolic acid derivatives tablets. BRAZ J PHARM SCI 2013. [DOI: 10.1590/s1984-82502013000200013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Mycophenolate mofetil (MMF) and mycophenolate sodium (MPS) are an ester and a salt of mycophenolic acid. They have different kinetic in vivo characteristics due to differences in molecular structures, physicochemical properties and formulations administered. In this study, dissolution profiles of reference products were tested in different media to evaluate the effect of pH, kinetic dissolution and the best statistical model that can be used to predict the release of both drugs. The drug release was determined by using a validated ultraviolet spectrophotometry method, λ 250 nm. The method showed to be selective, linear, precise and accurate for MMF in 0.1 M HCl and MPS in sodium phosphate buffer pH 6.8. Dissolution kinetics models of zero order, first order, Higuchi, Hixson-Crowell and Weibull were applied to data in order to select the best fit by linear regression. The regression parameters were estimated and the models were evaluated with the results of residuals and coefficient of determination. The residuals obtained from dissolution kinetics models were random, uncorrelated, and normally distributed with constant variance. The R² values (74.7% for MMF and 95.8% for MPS) demonstrated good ability of the Weibull regression to explain the variability and to predict the drugs' release.
Collapse
|
|
39
|
Doria C, Greenstein S, Narayanan M, Ueda K, Wiland A, McCague K, Sankari B, Chan L. Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry. Clin Transplant 2012; 26:E602-11. [PMID: 23121178 PMCID: PMC3556697 DOI: 10.1111/ctr.12035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2012] [Indexed: 01/30/2023]
Abstract
Background Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking. Methods Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg). Results The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p = 0.02]; month 12, 47.3% vs. 39.4% [p = 0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose >2000 mg (p = 0.029) vs. 2000 mg. Conclusions These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.
Collapse
Affiliation(s)
- Cataldo Doria
- Department of Transplant Surgery, Thomas Jefferson University Hospital, Philadelphia, PA 19107-5563, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Coyne JD, Campbell F. Microscopic features associated with mycophenolate mofetil in gastric and colonic biopsies. Histopathology 2012; 61:993-7. [DOI: 10.1111/j.1365-2559.2012.04305.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
41
|
Kamińnska J, Sobiak J, Głyda M, Duda G, Nogala-Kałucka M, Siger A, Chrzanowska M. Effect of clinical condition and mycophenolate mofetil on plasma retinol, α-tocopherol and β-carotene in renal transplant recipients. Arch Med Sci 2012; 8:256-62. [PMID: 22661998 PMCID: PMC3361038 DOI: 10.5114/aoms.2012.28553] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2011] [Revised: 09/15/2011] [Accepted: 01/14/2012] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Plasma antioxidant vitamins (retinol, α-tocopherol, β-carotene) were measured to establish the influence of clinical condition and mycophenolate mofetil (MMF) treatment on the nutritional status of renal transplant recipients. MATERIAL AND METHODS In 106 adult patients plasma vitamins were measured and 24-h diet history questionnaires were conducted. The MMF influence on plasma vitamins was verified in 61 patients. RESULTS The current dietary intakes of vitamins in daily food rations were lower than recommended. Plasma retinol was lower in patients suffering from gastrointestinal disorders (1.25 ±0.48 mg/l vs. 1.55 ±0.70 mg/l) and inversely associated with aminotransferases activity (p = 0.019) and creatinine clearance (p = 0.021). Retinol concentrations were positively associated with plasma creatinine (p = 0.027) and pharmacokinetic parameters of MMF phenyl glucuronide. β-Carotene concentrations were higher in women (0.39 ±0.46 mg/l vs. 0.28 ±0.23 mg/l; p = 0.041) and when MMF was co-administered with cyclosporine vs. tacrolimus (0.45 ±0.62 mg/l vs. 0.25 ±0.19 mg/l). Plasma α-tocopherol correlated negatively with the mycophenolic acid pre-dose concentration (p = 0.027) and was significantly lower in patients treated with calcineurin inhibitors (8.90 ±5.23 mg/l vs. 12.25 ±5.62 mg/l). A positive correlation was observed between α-tocopherol levels and aspartate aminotransferase (p = 0.006). In multivariate regression aspartate aminotransferase and MMF treatment significantly influenced retinol (p < 0.001). CONCLUSIONS The MMF treatment was associated with significantly lower retinol concentrations. The gastrointestinal disorders occurrence in MMF-treated patients may cause a decrease in retinol absorption. Diet adjustment and/or vitamin A supplementation should be considered.
Collapse
Affiliation(s)
- Jolanta Kamińnska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| | - Joanna Sobiak
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| | - Maciej Głyda
- Department of Transplantology and General Surgery, District Hospital, Poznan, Poland
| | - Grażyna Duda
- Department of Bromatology, Poznan University of Medical Sciences, Poland
| | | | - Aleksander Siger
- Department of Biochemistry and Food Analysis, Poznan University of Life Sciences, Poland
| | - Maria Chrzanowska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| |
Collapse
|
|
42
|
Kamińska J, Głyda M, Sobiak J, Chrzanowska M. Pharmacokinetics of mycophenolic acid and its phenyl glucuronide metabolite in kidney transplant recipients with renal impairment. Arch Med Sci 2012; 8:88-96. [PMID: 22457681 PMCID: PMC3309443 DOI: 10.5114/aoms.2012.27287] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2010] [Revised: 09/15/2010] [Accepted: 10/25/2010] [Indexed: 02/02/2023] Open
Abstract
INTRODUCTION The aim of the study was to analyse the influence of renal impairment on the pharmacokinetic parameters (PK) of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in renal transplant recipients. MATERIAL AND METHODS The study included 43 adult patients during the maintenance period (> 6 months) following renal transplantation, treated with mycophenolate mofetil (MMF), calcineurin inhibitors (CNI) (tacrolimus or cyclosporine) and steroids. The study compared patients with normal renal function (n = 17; creatinine clearance (C(cr)) > 60 ml/min) and with renal impairment (n = 26; C(cr) < 60 ml/min). Areas under the 4-h curve (AUC(0-4 h)) of MPA and MPAG were determined using a validated HPLC method. RESULTS The renal impairment group showed significantly increased AUC(0-4 h) and pre-dose (C(0)) for MPAG compared to patients with normal renal function and increased MPA C(0). However, there was no significant difference in MPA AUC(0-4 h) between patients with renal impairment and patients with normal renal function. In multivariate analysis some MPA and MPAG PK parameters were correlated with sex, CNI co-administered and body weight. CONCLUSIONS Although MPAG is an inactive metabolite, its accumulation in patients with renal impairment can be unfavourable. The results of our study indicate that solely MPA C(0) determination in patients receiving MMF may be insufficient in clinical practice because of great inter-patient variability of this PK parameter caused mainly by enterohepatic recirculation.
Collapse
Affiliation(s)
- Jolanta Kamińska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| | - Maciej Głyda
- Department of Transplantology, District Hospital, Poznań, Poland
| | - Joanna Sobiak
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| | - Maria Chrzanowska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Poland
| |
Collapse
|
|
43
|
Kamińska J, Sobiak J, Suliburska JM, Duda G, Głyda M, Krejpcio Z, Chrzanowska M. Effect of mycophenolate mofetil on plasma bioelements in renal transplant recipients. Biol Trace Elem Res 2012; 145:136-43. [PMID: 21870152 PMCID: PMC3272225 DOI: 10.1007/s12011-011-9178-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 08/12/2011] [Indexed: 11/25/2022]
Abstract
The proper concentrations of plasma bioelements may favorably reduce the incidence of metabolic disorders, which often occur during immunosuppressive therapy. Mycophenolate mofetil (MMF) is currently one of the most frequently administered immunosuppressive agents; however, MMF treatment is often related to gastrointestinal side effects. The aim of this study was thus to verify whether the MMF treatment itself, or its metabolite pharmacokinetics, has an effect on the concentrations of plasma bioelements. To determine this, the effect of MMF on the levels of both major (sodium [Na], potassium [K], calcium [Ca], magnesium [Mg]), and trace (iron [Fe], zinc [Zn], copper [Cu]) plasma bioelements in 61 renal transplant recipients was assessed in comparison to a control group (n = 45). The pharmacokinetic parameters of mycophenolic acid were determined by the high-performance liquid chromatography method. All patients filled out a 24-h diet history questionnaire. The results showed high plasma concentrations of Fe and low plasma concentrations of Mg and Zn as compared with diagnostic norms. The patients treated with MMF had significantly lower plasma Na (P < 0.001) and significantly higher plasma Zn (P = 0.030) and Cu concentrations (P < 0.001). In conclusion, MMF treatment was found to affect plasma Fe, Zn, and Cu levels by increasing their concentrations while decreasing the plasma Na concentration. Mg and Zn deficiencies, as well as excessive Fe levels, are frequently observed irrespective of the immunosuppressive regimen applied, which suggests that monitoring of these bioelements may be favorable.
Collapse
Affiliation(s)
- Jolanta Kamińska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznań, Poland
| | - Joanna Sobiak
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznań, Poland
| | - Joanna Maria Suliburska
- Department of Human Nutrition and Hygiene, Poznań University of Life Sciences, 31, Wojska Polskiego Street, 60-624 Poznań, Poland
| | - Grażyna Duda
- Department of Bromatology, Poznan University of Medical Sciences, 42, Marcelińska Street, 61-354 Poznań, Poland
| | - Maciej Głyda
- Department of Transplantology, District Hospital, 7/19, Juraszów Street, 60-479 Poznań, Poland
| | - Zbigniew Krejpcio
- Department of Human Nutrition and Hygiene, Poznań University of Life Sciences, 31, Wojska Polskiego Street, 60-624 Poznań, Poland
| | - Maria Chrzanowska
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6, Święcickiego Street, 60-781 Poznań, Poland
| |
Collapse
|
|
44
|
Nakanishi T, Kozuki Y, Eikyu Y, Kubo K, Kawato Y, Marui T, Seki N, Masunaga T, Tamura K, Morokata T. In vitro and in vivo characterization of AS2643361, a novel and highly potent inosine 5'-monophosphate dehydrogenase inhibitor. Eur J Pharmacol 2011; 674:58-63. [PMID: 22075081 DOI: 10.1016/j.ejphar.2011.10.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 10/11/2011] [Accepted: 10/27/2011] [Indexed: 01/01/2023]
Abstract
Inosine 5'-monophosphate (IMP) dehydrogenase is a critical target in solid organ transplantation. To this end, the development of mycophenolate mofetil (MMF) represents a major advance in transplant medicine. Here, we investigated the in vitro and in vivo pharmacological effects of a novel IMP dehydrogenase inhibitor, AS2643361, in several immunological and non-immunological models. The in vitro inhibitory activity of AS2643361 on immune cell and endothelial cell proliferation and on antibody production from lipopolysaccharide-stimulated B cells, was significantly more potent than that of mycophenolic acid, the active form of MMF, despite the similar potency of these compounds on IMP dehydrogenase. In a rat heterotopic cardiac transplant model, monotherapy using orally administered AS2643361 at 10 or 20mg/kg/day prolonged the median graft survival time from 6 to 16 and 19days, respectively. In dinitrophenol-lipopolysaccharide stimulated rats, oral administration of AS2643361 at 2.5, 5 or 10mg/kg/day resulted in suppression of antibody production. In vivo antibody production against alloantigen was also suppressed by AS2643361 treatment at 5 or 10mg/kg/day. Furthermore, treatment with AS2543361 effectively inhibited balloon injury induced-intimal thickening, which is a major cause of late allograft loss. Overall, the in vivo activity of AS2643361 was over two-fold more potent than that of MMF. In addition, gastrointestinal toxicity, considered a dose-limiting factor for MMF, was reduced with AS2643361 treatment. These results suggest AS2643361 has higher potency and less toxicity than MMF, making it a potential candidate for treatment of acute and chronic rejection in transplant medicine.
Collapse
Affiliation(s)
- Tomonori Nakanishi
- Astellas Research Institute of America LLC, Transplantation Immunology, Skokie, IL 60077, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Barau C, Barrail-Tran A, Hemerziu B, Habes D, Taburet AM, Debray D, Furlan V. Optimization of the dosing regimen of mycophenolate mofetil in pediatric liver transplant recipients. Liver Transpl 2011; 17:1152-8. [PMID: 21695772 DOI: 10.1002/lt.22364] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mycophenolate mofetil (MMF) is now commonly used in pediatric liver transplant recipients, but no clear recommendations about the dosing regimen have been made for this population. The aim of this study was to determine the MMF dosage required for pediatric liver transplant recipients to achieve an area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12) ) for mycophenolic acid (MPA) greater than 30 mg hour/L. A pharmacokinetic study of 15 children (median age = 8.3 years, range = 1.1-15.2 years) was performed at a median of 11.0 months (range = 0.5-88.0 months) after liver transplantation. MMF was initially introduced at a median starting dose of 300 mg/m(2) twice a day (range = 186-554 mg/m(2) twice a day). Thirteen of the 15 patients had an MPA AUC(0-12) value less than 30 mg hour/L. The MMF dosage had to be increased in all patients except 1. The MMF dosage required to reach an MPA AUC(0-12) value greater than the defined target of 30 mg hour/L ranged from 371 to 1014 mg/m(2) /day. For 2 patients who received rifampin in addition to MMF, the MPA AUC(0-12) value remained low despite a 2-fold increase in the MMF dosage. In conclusion, an initial MMF dose of 600 mg/m(2) twice a day led to MPA AUC(0-12) values greater than the 30 mg hour/L threshold except when rifampin was coadministered. Because of the important interindividual variability of MPA pharmacokinetics, therapeutic drug monitoring is recommended for optimizing the daily MMF dosage. Furthermore, these results suggest that the coadministration of MPA with rifampin should be avoided.
Collapse
Affiliation(s)
- Caroline Barau
- Department of Clinical Pharmacy, Bicetre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Malekinejad H, Cheraghi H, Alizadeh A, Khadem-Ansari M, Tehrani A, Varasteh S. Nitric Oxide and Acute Phase Proteins Are Involved in Pathogenesis of Mycophenolate Mofetil–Induced Gastrointestinal Disorders in Rats. Transplant Proc 2011; 43:2741-6. [DOI: 10.1016/j.transproceed.2011.04.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2011] [Accepted: 04/19/2011] [Indexed: 10/17/2022]
|
|
47
|
Christians U, Klawitter J, Klawitter J, Brunner N, Schmitz V. Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions. Expert Opin Drug Metab Toxicol 2011; 7:175-200. [PMID: 21241200 DOI: 10.1517/17425255.2011.544249] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION A major challenge in transplantation is improving long-term organ transplant and patient survival. Immunosuppressants protect the transplant organ from alloimmune reactions, but sometimes also exhibit limiting side effects. The key to improving long-term outcome following transplantation is the selection of the correct immunosuppressive regimen for an individual patient for minimizing toxicity while maintaining immunosuppressive efficacy. AREAS COVERED Proteomics and metabolomics have the potential to develop sensitive and specific diagnostic tools for monitoring early changes in cell signal transduction, regulation and biochemical pathways. Here, we review the steps required for the development of molecular markers from discovery, mechanistic and clinical qualification to regulatory approval, and present a critical discussion of the current status of molecular marker development as relevant for the management and individualization of immunosuppressive drug regimens. EXPERT OPINION Although metabolomics and proteomics-based studies have yielded several candidate molecular markers, most published studies are poorly designed, statistically underpowered and/or often have not gone beyond the discovery stage. Most molecular marker candidates are still at an early stage. Due to the high complexity of and the resources required for diagnostic marker development, initiatives and consortia organized and supported by funding agencies and regulatory agencies will be critical.
Collapse
Affiliation(s)
- Uwe Christians
- University of Colorado, Department of Anesthesiology, 1999 North Fitzsimons Parkway, Bioscience East, Suite 100, Aurora, CO 80045-7503, USA.
| | | | | | | | | |
Collapse
|
|
48
|
Bolin P, Gohh R, Kandaswamy R, Shihab FS, Wiland A, Akhlaghi F, Melancon K. Mycophenolic acid in kidney transplant patients with diabetes mellitus: does the formulation matter? Transplant Rev (Orlando) 2011; 25:117-23. [DOI: 10.1016/j.trre.2010.12.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 11/18/2010] [Accepted: 12/21/2010] [Indexed: 10/18/2022]
|
|
49
|
Carvalho R, Almeida N, Portela F, Gomes D, Gregório C, Gouveia H, Sofia C. Terminal ileitis in a renal transplanted patient: could it be infectious ileitis, Crohn's disease, or pharmacological toxicity? Inflamm Bowel Dis 2011; 17:E52-3. [PMID: 21456034 DOI: 10.1002/ibd.21701] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 02/03/2011] [Indexed: 12/09/2022]
|
|
50
|
The proton pump inhibitor pantoprazole and its interaction with enteric-coated mycophenolate sodium in transplant recipients. J Heart Lung Transplant 2011; 30:565-71. [DOI: 10.1016/j.healun.2010.12.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 11/03/2010] [Accepted: 12/03/2010] [Indexed: 11/22/2022] Open
|