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Guo G, Ke M, Xu J, Wu W, Chen J, Ke C, Huang P, Lin C. Physiologically based pharmacokinetic model of sodium-glucose cotransporter 2 inhibitors predicted pharmacokinetics and pharmacodynamics to explore dosage regimen for patients with type 2 diabetes mellitus and renal insufficiency. Front Pharmacol 2025; 16:1520268. [PMID: 40230691 PMCID: PMC11994927 DOI: 10.3389/fphar.2025.1520268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 03/17/2025] [Indexed: 04/16/2025] Open
Abstract
Objective This study aimed to compare the hypoglycemic effects of four SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin), simulate the 24-h urinary glucose excretion (UGE) of these inhibitors in T2DM patients with renal insufficiency, and investigate optimal dosage regimen for the SGLT2 inhibitor in these patients. Method We established a physiologically based pharmacokinetic (PBPK) model of SGLT2 inhibitors using the PK-Sim software, and the renal physiological tissue structure was expanded to include renal tubules using the MoBi software. The PBPK/PD (pharmacodynamics) model of SGLT2 inhibitors was validated following comparison of the observed plasma concentration and pharmacokinetic parameters. Result The model simulation results showed that 71.4% of the predicted pharmacokinetic parameters AUC (area under the curve) and Cmax (peak concentration) closely matched the observed values within 0.8-1.3 folds accuracy. Further, 83.9% of the predicted concentration-time curves and 84.65% of the predicted 24-h urinary glucose excretion aligned with the observed data points within 0.5-2 folds accuracy. The MPE, AFE and AAFE values for all concentration-time data points were 0.90, 1.07 and 1.08, indicating that the predictive performance of the PBPK/PD model was robust and reliable. It was predicted that optimal hypoglycemic effects would be achieved in T2DM patients with mild, moderate, and severe renal insufficiency, when treated with ipragliflozin 50 mg qd, dapagliflozin 10 mg qd or canagliflozin 100 mg qd, empagliflozin 10 mg, respectively. Conclusion This study provided a scientific basis for optimizing the dosage regimen in T2DM patients with renal insufficiency.
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Affiliation(s)
- Guimu Guo
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Meng Ke
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jianwen Xu
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Wanhong Wu
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jiarui Chen
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Chengjie Ke
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Pinfang Huang
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Cuihong Lin
- Department of Pharmacy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Shahidehpour A, Rashid M, Askari MR, Ahmadasas M, Abdel-Latif M, Fritschi C, Quinn L, Reutrakul S, Bronas UG, Cinar A. Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease. AAPS J 2024; 26:94. [PMID: 39160349 DOI: 10.1208/s12248-024-00962-2] [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: 05/10/2024] [Accepted: 07/27/2024] [Indexed: 08/21/2024] Open
Abstract
Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.
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Affiliation(s)
- Andrew Shahidehpour
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Mudassir Rashid
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Mohammad Reza Askari
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Mohammad Ahmadasas
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Mahmoud Abdel-Latif
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA
| | - Cynthia Fritschi
- Department of Biobehavioral Nursing Science, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Lauretta Quinn
- Department of Biobehavioral Nursing Science, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Sirimon Reutrakul
- College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Ulf G Bronas
- School of Nursing and Rehabilitation Medicine, Columbia University in New York City, New York, New York, USA
| | - Ali Cinar
- Department of Chemical and Biological Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
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Jeong SI, Ban MS, Hwang JG, Park MK, Lim S, Kim S, Kwon SK, Kim Y, Cho JM, Na JJ, Huh W, Chung JY. The effect of renal function on the pharmacokinetics and pharmacodynamics of enavogliflozin, a potent and selective sodium-glucose cotransporter-2 inhibitor, in type 2 diabetes. Diabetes Obes Metab 2024; 26:2588-2597. [PMID: 38618974 DOI: 10.1111/dom.15573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 04/16/2024]
Abstract
AIMS To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.
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Affiliation(s)
- Sae Im Jeong
- Department of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, Cheongju-si, Republic of Korea
| | - Mu Seong Ban
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
| | - Jun-Gi Hwang
- Department of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, Cheongju-si, Republic of Korea
| | - Min-Kyu Park
- Department of Clinical Pharmacology and Therapeutics, Chungbuk National University College of Medicine and Hospital, Cheongju-si, Republic of Korea
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sejoong Kim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Soon Kil Kwon
- Department of Internal Medicine, Chungbuk National University College of Medicine and Hospital, Cheongju-si, Republic of Korea
| | - Yoonjin Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
| | - Jae Min Cho
- Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea
| | - Jae Jin Na
- Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea
| | - Wan Huh
- Clinical Development Center, Daewoong Pharmaceutical Co., Ltd., Seoul, Republic of Korea
| | - Jae-Yong Chung
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of Korea
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Trepiccione F, Iervolino A, D'Acierno M, Siccardi S, Costanzo V, Sardella D, De La Motte LR, D'Apolito L, Miele A, Perna AF, Capolongo G, Zacchia M, Frische S, Nielsen R, Staiano L, Sambri I, De Cegli R, Unwin R, Eladari D, Capasso G. The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI. Sci Transl Med 2023; 15:eabn4214. [PMID: 37910600 DOI: 10.1126/scitranslmed.abn4214] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 10/10/2023] [Indexed: 11/03/2023]
Abstract
Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.
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Affiliation(s)
- Francesco Trepiccione
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Anna Iervolino
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | | | - Sabrina Siccardi
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Vincenzo Costanzo
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Donato Sardella
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Luigi R De La Motte
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Luciano D'Apolito
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Antonio Miele
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
| | - Alessandra F Perna
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | - Giovanna Capolongo
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | - Miriam Zacchia
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
| | | | - Rikke Nielsen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
| | - Leopoldo Staiano
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
- Institute for Genetic and Biomedical Research, National Research Council (CNR), 20089 Milan, Italy
| | - Irene Sambri
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
- Department of Medical and Translational Science, Federico II University, 80131 Naples, Italy
| | - Rossella De Cegli
- Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
| | - Robert Unwin
- UCL Department of Renal Medicine, Royal Free Hospital, London NW3 2PF, UK
| | - Dominique Eladari
- Service de Médecine de Précision des maladies Métaboliques et Rénales, CHU Amiens-Picardie, Université de Picardie Jules Verne, 80054 Amiens, France
- FCRIN-INI-CRCT, 54500 Vandœuvre-lès-Nancy, France
- Paris Cardiovascular Research Center (PARCC), INSERM U970, F-75015, Paris, France
| | - Giovambattista Capasso
- Department of Medical Translational Sciences, University of Campania "Luigi Vanvitelli," 80131 Naples, Italy
- Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, Italy
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Du W, Hu J, Liang J, Yang X, Fang B, Ma G. Effect of Astragali radix extract on pharmacokinetic behavior of dapagliflozin in healthy and type 2 diabetic rats. Front Pharmacol 2023; 14:1214658. [PMID: 37881186 PMCID: PMC10597649 DOI: 10.3389/fphar.2023.1214658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 09/22/2023] [Indexed: 10/27/2023] Open
Abstract
Objective: This study aimed to investigate effect of antidiabetic herb Astragali Radix (AR) on pharmacokinetic behavior of dapagliflozin (DAPA) in healthy rats and type 2 diabetes mellitus (T2DM) rats. Methods: The T2DM rats were induced by high-fat diet (HFD) and intraperitoneal injection of streptozotocin (STZ). Concentrations of DAPA in healthy and T2DM rat plasma were determined by UPLC-MS/MS method. Effect of AR extract (ARE) on pharmacokinetic behavior of DAPA in healthy and T2DM rats was evaluated, respectively. Results: The diabetes status and co-administrated with ARE significantly affected pharmacokinetic behaviors of DAPA in the rats. Compared to that in healthy rats, t max of DAPA significantly shortened, its C max significantly increased in T2DM rats, and its t 1/2, V, AUC, CL and MRT kept unchanged. When ARE was co-administrated with DAPA, C max of DAPA significantly increased, its t max and MRT significantly decreased, and its t 1/2, V, AUC and CL kept unchanged in healthy rats. t max and C max of DAPA significantly decreased, its t 1/2 and V significantly increased, and its AUC, CL and MRT were unchanged in T2DM rats when ARE was co-administrated with DAPA. Co-administration of DAPA and ARE promoted absorptive rate of DAPA, increased its extravascular tissue distribution, and prolonged its duration of action. ARE did not cause accumulation of DAPA in vivo. Conclusion: Both disease status of T2DM and co-administration of ARE affect pharmacokinetic behavior of DAPA in vivo. Potential pharmacokinetic interactions may occur in vivo when herbs and drugs are co-administrated, which may affect efficacy and safety of drugs.
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Affiliation(s)
| | | | | | | | | | - Guo Ma
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
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Barreto J, Borges C, Rodrigues TB, Jesus DC, Campos-Staffico AM, Nadruz W, Luiz da Costa J, Bueno de Oliveira R, Sposito AC. Pharmacokinetic Properties of Dapagliflozin in Hemodialysis and Peritoneal Dialysis Patients. Clin J Am Soc Nephrol 2023; 18:1051-1058. [PMID: 37227937 PMCID: PMC10564347 DOI: 10.2215/cjn.0000000000000196] [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: 02/03/2023] [Accepted: 05/17/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors attenuate incident cardiovascular outcomes, irrespective of baseline GFR, in conservatively managed CKD. As this condition inexorably progresses to demanding KRT, drug withdrawal is supported by the current lack of evidence of safety of SGLT2 inhibitors in dialysis. METHODS This study was a prospective, single-center, open-label trial ( ClinicalTrials.gov identifier: NCT05343078 ) aimed at assessing the pharmacokinetic properties and safety of dapagliflozin in patients with kidney failure on regular dialysis regimens compared with those with type 2 diabetes and age- and sex-matched controls with normal kidney function. Peripheral blood samples were collected from both groups every 30 minutes for 4 hours and again after 48 hours after ingestion of dapagliflozin 10 mg, which occurred immediately before dialysis session initiation in the kidney failure group. This protocol occurred in drug-naïve patients and again after six daily doses of dapagliflozin to assess whether the drug had accumulated. The plasma and dialysate levels of dapagliflozin at each time point were determined by liquid chromatography and used to calculate pharmacokinetics parameters (peak concentration [C max ] and area under the plasma concentration-versus-time curve) for each participant. RESULTS Dapagliflozin C max was 117 and 97.6 ng/ml in the kidney failure and control groups, respectively, whereas the corresponding accumulation ratios were 26.7% and 9.5%. No serious adverse events were reported for either group. Dapagliflozin recovered from dialysate corresponded to 0.10% of the administered dose. CONCLUSIONS In patients with kidney failure on dialysis, dapagliflozin was well tolerated, was slightly dialyzable, and had nonaccumulating pharmacokinetic properties. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Pharmacokinetics and Dialyzability of Dapagliflozin in Dialysis Patients (DARE-ESKD 1), NCT05343078.
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Affiliation(s)
- Joaquim Barreto
- Laboratory of Atherosclerosis and Vascular Biology (Aterolab), Cardiology Division, University of Campinas (Unicamp), Campinas, Brazil
| | - Cynthia Borges
- Laboratory for Evaluation of Mineral and Bone Disorders in Nephrology (LEMON), Nephrology Division, University of Campinas (Unicamp), Campinas, Brazil
| | - Tais Betoni Rodrigues
- Campinas Poison Control Center (CIATOX), School of Medical Sciences, University of Campinas (Unicamp), Campinas, Brazil
| | - Daniel C. Jesus
- Laboratory of Atherosclerosis and Vascular Biology (Aterolab), Cardiology Division, University of Campinas (Unicamp), Campinas, Brazil
| | | | - Wilson Nadruz
- Cardiology Division, Clinics Hospital, University of Campinas (Unicamp), Campinas, Brazil
| | - Jose Luiz da Costa
- Campinas Poison Control Center (CIATOX), School of Medical Sciences, University of Campinas (Unicamp), Campinas, Brazil
- Faculty of Pharmaceutical Sciences, University of Campinas (Unicamp), Campinas, Brazil
| | - Rodrigo Bueno de Oliveira
- Laboratory for Evaluation of Mineral and Bone Disorders in Nephrology (LEMON), Nephrology Division, University of Campinas (Unicamp), Campinas, Brazil
| | - Andrei C. Sposito
- Laboratory of Atherosclerosis and Vascular Biology (Aterolab), Cardiology Division, University of Campinas (Unicamp), Campinas, Brazil
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St Peter WL, Meaney CJ. Extending SGLT2 Inhibitor Use for People Undergoing Dialysis? Clin J Am Soc Nephrol 2023; 18:991-993. [PMID: 37418254 PMCID: PMC10564363 DOI: 10.2215/cjn.0000000000000232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/08/2023]
Affiliation(s)
- Wendy L St Peter
- College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Calvin J Meaney
- University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York
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Miners JO, Polasek TM, Hulin JA, Rowland A, Meech R. Drug-drug interactions that alter the exposure of glucuronidated drugs: Scope, UDP-glucuronosyltransferase (UGT) enzyme selectivity, mechanisms (inhibition and induction), and clinical significance. Pharmacol Ther 2023:108459. [PMID: 37263383 DOI: 10.1016/j.pharmthera.2023.108459] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/03/2023]
Abstract
Drug-drug interactions (DDIs) arising from the perturbation of drug metabolising enzyme activities represent both a clinical problem and a potential economic loss for the pharmaceutical industry. DDIs involving glucuronidated drugs have historically attracted little attention and there is a perception that interactions are of minor clinical relevance. This review critically examines the scope and aetiology of DDIs that result in altered exposure of glucuronidated drugs. Interaction mechanisms, namely inhibition and induction of UDP-glucuronosyltransferase (UGT) enzymes and the potential interplay with drug transporters, are reviewed in detail, as is the clinical significance of known DDIs. Altered victim drug exposure arising from modulation of UGT enzyme activities is relatively common and, notably, the incidence and importance of UGT induction as a DDI mechanism is greater than generally believed. Numerous DDIs are clinically relevant, resulting in either loss of efficacy or an increased risk of adverse effects, necessitating dose individualisation. Several generalisations relating to the likelihood of DDIs can be drawn from the known substrate and inhibitor selectivities of UGT enzymes, highlighting the importance of comprehensive reaction phenotyping studies at an early stage of drug development. Further, rigorous assessment of the DDI liability of new chemical entities that undergo glucuronidation to a significant extent has been recommended recently by regulatory guidance. Although evidence-based approaches exist for the in vitro characterisation of UGT enzyme inhibition and induction, the availability of drugs considered appropriate for use as 'probe' substrates in clinical DDI studies is limited and this should be research priority.
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Affiliation(s)
- John O Miners
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia.
| | - Thomas M Polasek
- Certara, Princeton, NJ, USA; Centre for Medicines Use and Safety, Monash University, Melbourne, Australia
| | - Julie-Ann Hulin
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Andrew Rowland
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Robyn Meech
- Discipline of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders University, Adelaide, Australia
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9
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van der Hoek S, Koomen JV, van Bommel EJM, Mosterd CM, Scholtes RA, Hesp AC, Stevens J, van Raalte DH, Heerspink HJL. Exposure-Response Analysis of the Sodium-Glucose Cotransporter-2 Inhibitors Dapagliflozin and Empagliflozin on Kidney Hemodynamics in Patients with Type 2 Diabetes. J Pers Med 2023; 13:jpm13050747. [PMID: 37240917 DOI: 10.3390/jpm13050747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/23/2023] [Accepted: 04/26/2023] [Indexed: 05/28/2023] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve markers for renal and cardiovascular outcomes in patients with and without type 2 diabetes (T2D). To assess whether individual differences in plasma drug exposure can explain inter-individual response variation, we characterized the exposure-response relationship for two SGLT2 inhibitors on several clinical and kidney hemodynamic variables. Data were obtained from two studies, RED and RECOLAR, assessing the effects of once-daily 10 mg dapagliflozin or empagliflozin, respectively, on kidney hemodynamics in patients with T2D. Individual plasma exposure was estimated using non-compartmental analyses and exposure-response relationships were assessed using linear mixed-effects models. In 23 patients participating in RED, the dapagliflozin geometric mean apparent area under the concentration-time curve during one dosing interval at steady state (AUC0-tau,ss) was 1153.1 µg/L*h (coefficient of variation (CV) 81.8%) and associated, per doubling, with decreases in body weight (0.29 kg, p < 0.001), systolic blood pressure (0.80 mmHg, p = 0.002), measured glomerular filtration rate (mGFR) (0.83 mL/min, p = 0.03), and filtration fraction (0.09%, p = 0.04). In 20 patients participating in RECOLOR, the empagliflozin geometric mean AUC0-tau,ss was 2035.7 nmol/L*h (CV 48.4%) and associated, per doubling, with decreases in body weight (0.13 kg, p = 0.002), systolic blood pressure (0.65 mmHg, p = 0.045), and mGFR (0.78 mL/min, p = 0.002). To conclude, dapagliflozin and empagliflozin plasma exposure was highly variable between patients and associated with inter-individual variation in response variables.
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Affiliation(s)
- Sjoukje van der Hoek
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Jeroen V Koomen
- Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Erik J M van Bommel
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
| | - Charlotte M Mosterd
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
| | - Rosalie A Scholtes
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
| | - Anne C Hesp
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
| | - Jasper Stevens
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Daniel H van Raalte
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, Location VUMC, Diabetes Center, De Boelelaan 1118, 1081 HZ Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, VU University, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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10
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Solomon J, Festa MC, Chatzizisis YS, Samanta R, Suri RS, Mavrakanas TA. Sodium-glucose co-transporter 2 inhibitors in patients with chronic kidney disease. Pharmacol Ther 2023; 242:108330. [PMID: 36513134 DOI: 10.1016/j.pharmthera.2022.108330] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
Diabetes drives an increasing burden of cardiovascular and renal disease worldwide, motivating the search for new hypoglycemic agents that confer cardiac and renal protective effects. Although initially developed as hypoglycemic agents, sodium-glucose co-transporter 2 (SGLT-2) inhibitors have since been studied in patients with and without diabetes for the management of heart failure and chronic kidney disease. A growing body of evidence supports the efficacy and safety of SGLT-2 inhibitors in patients with chronic kidney disease (CKD), based on complex mechanisms of action that extend far beyond glucosuria and that confer beneficial effects on cardiovascular and renal hemodynamics, fibrosis, inflammation, and end-organ protection. This review focuses on the pharmacology and pathophysiology of SGLT-2 inhibitors in patients with CKD, as well as their cardiovascular and renal effects in this population. We are focusing on the five agents that have been tested in cardiovascular outcome trials and that have been approved either in Europe or in North America: empagliflozin, dapagliflozin, canagliflozin, ertugliglozin, and sotagliflozin.
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Affiliation(s)
- Joshua Solomon
- Division of Internal Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Maria Carolina Festa
- Division of Internal Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Yiannis S Chatzizisis
- Division of Cardiovascular Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Ratna Samanta
- Division of Nephrology, Department of Medicine, McGill University Health Center, Montreal, QC, Canada
| | - Rita S Suri
- Division of Nephrology, Department of Medicine, McGill University Health Center, Montreal, QC, Canada; Research Institute of the McGill University Health Center, Montreal, QC, Canada
| | - Thomas A Mavrakanas
- Division of Nephrology, Department of Medicine, McGill University Health Center, Montreal, QC, Canada; Research Institute of the McGill University Health Center, Montreal, QC, Canada.
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11
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Eleftheriadis T, Pissas G, Filippidis G, Efthymiadi M, Liakopoulos V, Stefanidis I. Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells. Int J Mol Sci 2022; 23:16107. [PMID: 36555751 PMCID: PMC9781434 DOI: 10.3390/ijms232416107] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/21/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Gliflozins are a new class of antidiabetic drugs with renoprotective properties. In cultures of primary human renal tubular epithelial cells (RPTECs) subjected to high-glucose conditions in the presence or absence of dapagliflozin, we evaluated cellular senescence pathways. High glucose increased sodium-glucose cotransporter-2 (SGLT-2) expression and glucose consumption, enhancing reactive oxygen species production. The latter induced DNA damage, ataxia telangiectasia mutated kinase (ATM), and p53 phosphorylation. Stabilized p53 increased the cell cycle inhibitor p21, resulting in cell cycle arrest and increasing the cellular senescence marker beta-galactosidase (GLB-1). RPTECs under high glucose acquired a senescence-associated secretory phenotype, which was detected by the production of IL-1β, IL-8, and TGF-β1. By decreasing SGLT-2 expression and glucose consumption, dapagliflozin inhibited the above pathway and prevented RPTEC senescence. In addition, dapagliflozin reduced the cell cycle inhibitor p16 independently of the glucose conditions. Neither glucose concentration nor dapagliflozin affected the epithelial-to-mesenchymal transition when assessed with α-smooth muscle actin (α-SMA). Thus, high glucose induces p21-dependent RPTEC senescence, whereas dapagliflozin prevents it. Since cellular senescence contributes to the pathogenesis of diabetic nephropathy, delineating the related molecular mechanisms and the effects of the widely used gliflozins on them is of particular interest and may lead to novel therapeutic approaches.
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12
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Shah N, Perkovic V, Kotwal S. Impact of SGLT2 inhibitors on the kidney in people with type 2 diabetes and severely increased albuminuria. Expert Rev Clin Pharmacol 2022; 15:827-842. [PMID: 35912871 DOI: 10.1080/17512433.2022.2108402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Diabetes is the most common cause of end stage kidney disease. Therapies such as sodium-glucose co-transporter-2 inhibitors have been identified over the last decade as effective oral hypoglycemic agents that also confer additional cardio and kidney protection. Knowledge of their mechanism of action and impact on patients with diabetes and albuminuria is vital in galvanizing prescriber confidence and increasing clinical uptake. AREAS COVERED This manuscript discusses the pathophysiology of diabetic kidney disease, patho-physiological mechanisms for sodium-glucose co-transporter-2 inhibitors, and their impact on patients with Type 2 diabetes mellitus and albuminuric kidney disease. EXPERT OPINION Sodium-glucose co-transporter-2 inhibitors reduce albuminuria with consequent benefits on cardiovascular and kidney outcomes in patients with diabetes and severe albuminuria. Whilst they have been incorporated into guidelines, the uptake of these agents into clinical practice has been slow. Increasing the uptake of these agents into clinical practice is necessary to improve outcomes for the large number of patients with diabetic kidney disease globally.
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Affiliation(s)
- Nasir Shah
- Faculty of Medicine, UNSW, Kensington, Sydney Australia 2052
| | - Vlado Perkovic
- Faculty of Medicine, UNSW, Kensington, Sydney Australia 2052.,The George Institute for Global Health, UNSW, 1 King Street, Newtown, Sydney, Australia 2042
| | - Sradha Kotwal
- The George Institute for Global Health, UNSW, 1 King Street, Newtown, Sydney, Australia 2042.,Prince of Wales Hospital, High Street, Sydney, Australia, 2031
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13
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Scheen AJ. Counteracting heart failure with diabetes drugs: a review into the pharmacokinetic and pharmacodynamic properties. Expert Opin Drug Metab Toxicol 2022; 18:381-393. [PMID: 35876091 DOI: 10.1080/17425255.2022.2105693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION : Heart failure (HF) is becoming a huge public health burden. New diabetes drugs for type 2 diabetes (T2D), sodium-glucose cotransporter type 2 inhibitors (SGLT2is), reduce the rate of hospitalization for HF in placebo-controlled trials. AREAS COVERED : Pharmacokinetics of dapagliflozin and empagliflozin (in presence of renal impairment and hepatic dysfunction, two comorbidities frequently associated with HF) and pharmacodynamic studies in patients with HF. Main HF outcomes in T2D patients with cardiovascular risk and in patients with reduced (HFrEF) or preserved (HFpEF) ejection fraction, with or without T2D, from DAPA-HF, EMPEROR-Reduced and EMPEROR-Preserved original findings and post hoc analyses. EXPERT OPINION : No clinically relevant changes are expected concerning SGLT2i pharmacokinetics in patients with HF while pharmacodynamic studies reported improvements in myocardium/vascular parameters, biomarkers and functional status. All SGLT2is showed a remarkable reduction in hospitalization for HF in patients with T2D and high cardiovascular risk. Furthermore, both dapagliflozin and empagliflozin improved the prognosis of patients with HFrEF, independently of the presence of T2D. Similar results were reported with empagliflozin in patients with HFpEF, to be confirmed with dapagliflozin in an ongoing trial (DELIVER). Thus, SGLT2is offer a new opportunity for the prevention and management of HF in patients with or without T2D.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Centre for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium.,Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
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14
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Doehner W, Anker SD, Butler J, Zannad F, Filippatos G, Ferreira JP, Salsali A, Kaempfer C, Brueckmann M, Pocock SJ, Januzzi JL, Packer M. Uric acid and sodium-glucose cotransporter-2 inhibition with empagliflozin in heart failure with reduced ejection fraction: the EMPEROR-reduced trial. Eur Heart J 2022; 43:3435-3446. [PMID: 35788657 PMCID: PMC9492270 DOI: 10.1093/eurheartj/ehac320] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 05/10/2022] [Accepted: 06/03/2022] [Indexed: 12/13/2022] Open
Abstract
Background The sodium-glucose cotransporter-2 inhibitor empagliflozin decreases the risk of cardiovascular death or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction. Empagliflozin reduces serum uric acid (SUA), but the relevance of this effect in patients with HF is unclear. This study aimed to investigate the effect of empagliflozin on SUA levels and the therapeutic efficacy of empagliflozin in relation to SUA. Methods The association between SUA and the composite primary outcome of cardiovascular death or hospitalization for worsening HF, its components, and all-cause mortality was investigated in 3676 patients of the EMPEROR-Reduced trial (98.6% of the study cohort). The treatment effect of empagliflozin was studied in relation to SUA as continuous variable, to clinical hyperuricaemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) and in subgroups of patients of tertiles of SUA. Results Hyperuricaemia was prevalent in 53% of patients with no sex differences. Elevated SUA (highest tertile, mean SUA 9.38 ± 1.49 mg/dL) was associated with advanced severity of HF and with worst outcome [composite outcome, hazard ratio (HR) 1.64 (95% confidence interval, CI 1.28–2.10); cardiovascular mortality, HR 1.98 (95% CI 1.35–2.91); all-cause mortality, HR 1.8 (95% CI 1.29–2.49), all P < 0.001] in multivariate adjusted analyses, as compared with the lowest tertile. SUA was reduced following treatment with empagliflozin at 4 weeks (vs. placebo: −1.12 ± 0.04 mg/dL, P < 0.0001) and remained lower throughout follow-up, with a similar reduction in all prespecified subgroups. Empagliflozin reduced events of clinically relevant hyperuricaemia (acute gout, gouty arthritis or initiation of anti-gout therapy) by 32% [HR 0.68 (95% CI 0.52–0.89), P = 0.004]. The beneficial effect of empagliflozin on the primary endpoint was independent of baseline SUA [HR 0.76 (95% CI 0.65–0.88), P < 0.001) and of the change in SUA at 4 weeks [HR 0.81 (95% CI 0.69–0.95), P = 0.012]. As a hypothesis-generating finding, an interaction between SUA and treatment effect suggested a benefit of empagliflozin on mortality (cardiovascular and all-cause mortality) in patients in elevated SUA (P for interaction = 0.005 and = 0.011, respectively). Conclusion Hyperuricaemia is common in HF and is an independent predictor of advanced disease severity and increased mortality. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricaemia. The benefit of empagliflozin on the primary outcome was observed independently of SUA.
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Affiliation(s)
- Wolfram Doehner
- Berlin Institute of Health Center for Regenerative Therapies, and Department of Cardiology (CVK), and German Centre for Cardiovascular Research Partner Site Berlin, and Center for Stroke Research Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Stefan D Anker
- Berlin Institute of Health Center for Regenerative Therapies, and Department of Cardiology (CVK), and German Centre for Cardiovascular Research Partner Site Berlin, and Center for Stroke Research Berlin, Charité Universitätsmedizin, Berlin, Germany
| | - Javed Butler
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX 75226 USA.,Department of Medicine, University of Mississippi School of Medicine, Jackson, MS 39216, USA
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy 54500, France
| | - Gerasimos Filippatos
- National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, 12461, Haidari Athens, Greece
| | - João Pedro Ferreira
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, U1116, CHRU de Nancy, F-CRIN INI-CRCT, Nancy 54500, France.,UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
| | - Afshin Salsali
- Heart Failure and Diabetes Global Development, Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Rd, Ridgefield, CT 06877, USA.,Faculty of Medicine, Rutgers University, New Brunswick, NJ 07103, USA
| | - Carolyn Kaempfer
- Faculty of Medicine, Rutgers University, New Brunswick, NJ 07103, USA.,mainanalytics GmbH, Sulzbach, Otto-Volger-Str. 3c, 65843 Sulzbach/Taunus, Germany
| | - Martina Brueckmann
- Boehringer Ingelheim International, Binger Str. 173, 55218 Ingelheim, Germany.,First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, 68167 Mannheim, Germany
| | - Stuart J Pocock
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - James L Januzzi
- Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Milton Packer
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.,Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas ,TX 75226 USA.,Imperial College, London SW7 2BX, UK
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15
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Kurata Y, Nangaku M. Dapagliflozin for the treatment of chronic kidney disease. Expert Rev Endocrinol Metab 2022; 17:275-291. [PMID: 35822873 DOI: 10.1080/17446651.2022.2099373] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/05/2022] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Sodium-dependent glucose cotransporter 2 (SGLT2) is a glucose transporter expressed on the proximal tubular cells, where it reabsorbs glucose from the glomerular filtrate. SGLT2 inhibitors (SGLT2is), initially developed as an antidiabetic drug, have recently attracted considerable attention because they have cardiorenal protective effects. Among SGLT2is, dapagliflozin was the first to demonstrate the renoprotective effect in patients with and without diabetes and has been approved for chronic kidney disease (CKD) treatment. AREAS COVERED This review covers the pharmacological characteristics and the clinical efficacy and safety profiles of dapagliflozin, including comparison with other SGLT2is and risk modification strategies. EXPERT OPINION In DAPA-CKD, dapagliflozin reduced the primary outcome (≥50% estimated glomerular filtration rate [eGFR] decline, end-stage kidney disease [ESKD], or renal or cardiovascular [CV] death) by 39% in CKD patients. This beneficial effect was consistent across prespecified subgroups, including those based on the presence of diabetes. Dapagliflozin also decreased the CV composite outcome and all-cause death by 29% and 31%, respectively. Although an increased risk of adverse events such as ketoacidosis and volume depletion has been reported, the robust renal and CV benefits of dapagliflozin are expected to outweigh potential risks. SGLT2is, including dapagliflozin, will constitute the mainstay of CKD treatment.
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Affiliation(s)
- Yu Kurata
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Japan
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16
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Scheen AJ. Pharmacokinetic/Pharmacodynamic Properties and Clinical Use of SGLT2 Inhibitors in Non-Asian and Asian Patients with Type 2 Diabetes and Chronic Kidney Disease. Clin Pharmacokinet 2021; 59:981-994. [PMID: 32201911 DOI: 10.1007/s40262-020-00885-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic kidney disease is a prevalent complication of type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a unique mode of action targeting the kidney. As their glucose-lowering potency declines with the reduction in estimated glomerular filtration rate, their clinical use in patients with T2DM with chronic kidney disease has been submitted to restriction. However, recent observations demonstrated that SGLT2is reduce the progression of renal impairment in patients with mild-to-moderate chronic kidney disease, with or without albuminuria. Furthermore, SGLT2is reduce the incidence of cardiovascular events in patients with T2DM at high cardiovascular risk, independently of baseline estimated glomerular filtration rate. Thus, recent guidelines recommend the prescription of SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease defined by an estimated glomerular filtration rate between ≥ 30 and < 90 mL/min/1.73 m2 and/or albuminuria. The present comprehensive review describes the pharmacokinetic/pharmacodynamic properties of SGLT2is commercialised worldwide and in Japan in patients with T2DM with mild, moderate and severe chronic kidney disease. Drug exposure increases when the estimated glomerular filtration rate declines but without a clear-cut relationship with the severity of chronic kidney disease and in a rather moderate amplitude that most often does not require a dose reduction in the presence of mild-to-moderate chronic kidney disease. The urinary glucose excretion steadily declines with the reduction in estimated glomerular filtration rate. This may explain a lower effect on glucose control, yet the positive effects on body weight and blood pressure still remain. The efficacy and safety of these SGLT2is are analysed among patients with stages 3a and 3b chronic kidney disease in placebo-controlled randomised clinical trials, with almost similar results in Asian and non-Asian individuals with T2DM. In summary, there is no reason not to prescribe SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease, especially if the aim is to benefit from cardiovascular and/or renal protection.
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Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium. .,Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, CHU Sart Tilman (B35), 4000, Liege 1, Belgium.
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17
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Ito H, Matsumoto S, Izutsu T, Kusano E, Kondo J, Inoue H, Antoku S, Yamasaki T, Mori T, Togane M. Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation. PLoS One 2021; 16:e0248577. [PMID: 33720983 PMCID: PMC7959360 DOI: 10.1371/journal.pone.0248577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/01/2021] [Indexed: 12/25/2022] Open
Abstract
Aims The safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment. Methods In total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups. Results The body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set. Conclusions Luseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events.
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Affiliation(s)
- Hiroyuki Ito
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
- * E-mail:
| | - Suzuko Matsumoto
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Takuma Izutsu
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Eiji Kusano
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Jiro Kondo
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Hideyuki Inoue
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Shinichi Antoku
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Tomoko Yamasaki
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Toshiko Mori
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
| | - Michiko Togane
- Department of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital, Edogawa, Tokyo, Japan
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18
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Kuang Y, Chai Y, Xu L, Wang Z, Liang L, Qiao X, Ye M. Glabrone as a specific UGT1A9 probe substrate and its application in discovering the inhibitor glycycoumarin. Eur J Pharm Sci 2021; 161:105786. [PMID: 33684484 DOI: 10.1016/j.ejps.2021.105786] [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: 10/11/2020] [Revised: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 10/22/2022]
Abstract
UDP-glucuronosyltransferase 1A9 (UGT1A9) is one of the most important UGT isoforms, and plays an important role in the metabolic elimination of therapeutic drugs via glucuronidation. Herbal medicines affecting the activity of UGT1A9 may influence the metabolism of related drugs, thus causing herb-drug interactions and even adverse effects. However, few methods are available to evaluate the activity of UGT1A9. In this study, a natural product glabrone was discovered as an isoform-specific probe substrate for UGT1A9. The Vmax and Km values of glabrone were 362.6 nmol/min/mg protein and 17.2 μM for human liver microsomes (HLMs), and 382.3 nmol/min/mg protein and 16.6 μM for recombinant human UGT1A9, respectively. Glabrone 7-O-glucuronide, the UGT1A9 metabolite of glabrone, was prepared by using a plant glucuronosyltransferase UGT88D1, and the structure was identified by NMR spectroscopy. Using glabrone as a probe, we established a rapid HPLC method to screen UGT1A9 inhibitors from 54 natural products isolated from the Chinese herbal medicine licorice. Among them, glycycoumarin was found as a potent UGT1A9 inhibitor with an IC50 value of 6.04 μM. In rats, the pretreatment of glycycoumarin (4 mg/kg, i.p.) for 3 days could remarkably increase the plasma concentrations of dapagliflozin while decrease the concentrations of dapagliflozin-O-glucuronide after administration of dapagliflozin (1 mg/kg, i.v.), which is mainly metabolized by UGT1A9. The results indicated the potential risk of herb-drug interactions between licorice and UGT1A9-metabolizing drugs.
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Affiliation(s)
- Yi Kuang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
| | - Yue Chai
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
| | - Lulu Xu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
| | - Zilong Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
| | - Lei Liang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China
| | - Xue Qiao
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
| | - Min Ye
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China; Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Peking University, 38 Xueyuan Road, Beijing 100191, China.
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19
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van der Aart-van der Beek AB, Koomen JV, Dekkers CCJ, Barbour SJ, Boulton DW, Gansevoort RT, Greasley PJ, Abdul Gafor AH, Laverman GD, Li Q, Lim SK, Stevens J, Vervloet MG, Singh S, Cattran DC, Reich HN, Cherney DZI, Heerspink HJL. Evaluation of the Pharmacokinetics and Exposure-Response Relationship of Dapagliflozin in Patients without Diabetes and with Chronic Kidney Disease. Clin Pharmacokinet 2021; 60:517-525. [PMID: 33587286 PMCID: PMC8016788 DOI: 10.1007/s40262-020-00956-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVE Dapagliflozin, a sodium-glucose co-transporter inhibitor, was originally developed as an oral glucose-lowering drug for the treatment of type 2 diabetes mellitus. Emerging data suggest that cardiovascular and kidney benefits extend to patients without diabetes. Limited pharmacological data are, however, available in patients without diabetes. We aimed to characterise the pharmacokinetic profile of dapagliflozin in patients with chronic kidney disease without type 2 diabetes. METHODS Plasma samples were collected in a randomised, placebo-controlled, double-blind, cross-over trial (DIAMOND, NCT03190694, n = 53) that assessed the effects of 10 mg of dapagliflozin in patients with a glomerular filtration rate ≥ 25 mL/min/1.73 m2 and proteinuria > 500 mg/day. Mixed-effects models were used to develop a pharmacokinetic model and to evaluate the association between plasma exposure and response. RESULTS Plasma concentrations (n = 430 observations) from 48 patients (mean age 50.8 years, mean glomerular filtration rate 57.9 mL/min/1.73 m2, median proteinuria 1115 mg/24 h) were best described using a two-compartment model with first-order elimination. Apparent clearance and volume of distribution were 11.7 (95% confidence interval 10.7-12.7) L/h and 44.9 (95% confidence interval 39.0-50.9) L, respectively. Median dapagliflozin plasma exposure was 740.9 ng h/mL (2.5th-97.5th percentiles: 434.0-1615.3). Plasma exposure increased with decreasing kidney function. Every 100-ng h/mL increment in dapagliflozin plasma exposure was associated with a decrease in the urinary albumin:creatinine ratio (β = - 2.8%, p = 0.01), glomerular filtration rate (β = - 0.5 mL/min/1.73 m2, p < 0.01) and systolic blood pressure (β = - 0.4 mmHg, p = 0.03). CONCLUSIONS The dapagliflozin plasma concentration-time profile in patients with non-diabetic kidney disease appears similar to the profile of patients with diabetic kidney disease described in the literature. Furthermore, the plasma exposure was associated with changes in risk markers for kidney disease.
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Affiliation(s)
- Annemarie B van der Aart-van der Beek
- Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.,Clinical Pharmacy, Martini Hospital, Groningen, The Netherlands
| | - Jeroen V Koomen
- Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands
| | - Claire C J Dekkers
- Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands
| | - Sean J Barbour
- Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - David W Boulton
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Ron T Gansevoort
- Department of Nephrology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Peter J Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Abdul Halim Abdul Gafor
- Department of Medicine, Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
| | - Gozewijn D Laverman
- Department of Internal Medicine, ZGT Hospital, Almelo and Hengelo, The Netherlands
| | - Qiang Li
- The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia
| | - Soo Kun Lim
- Division of Nephrology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jasper Stevens
- Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology and Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Sunita Singh
- Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada
| | - Daniel C Cattran
- Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada
| | - Heather N Reich
- Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University Health Network and University of Toronto, Toronto, ON, Canada
| | - Hiddo J L Heerspink
- Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.
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20
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Pilla Reddy V, El‐Khateeb E, Jo H, Giovino N, Lythgoe E, Sharma S, Tang W, Jamei M, Rastomi‐Hodjegan A. Pharmacokinetics under the COVID-19 storm. Br J Clin Pharmacol 2021; 89:158-186. [PMID: 33226664 PMCID: PMC7753415 DOI: 10.1111/bcp.14668] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/26/2020] [Accepted: 11/06/2020] [Indexed: 12/27/2022] Open
Abstract
AIMS The storm-like nature of the health crises caused by COVID-19 has led to unconventional clinical trial practices such as the relaxation of exclusion criteria. The question remains: how can we conduct diverse trials without exposing subgroups of populations to potentially harmful drug exposure levels? The aim of this study was to build a knowledge base of the effect of intrinsic/extrinsic factors on the disposition of several repurposed COVID-19 drugs. METHODS Physiologically based pharmacokinetic (PBPK) models were used to study the change in the pharmacokinetics (PK) of drugs repurposed for COVID-19 in geriatric patients, different race groups, organ impairment and drug-drug interactions (DDIs) risks. These models were also used to predict epithelial lining fluid (ELF) exposure, which is relevant for COVID-19 patients under elevated cytokine levels. RESULTS The simulated PK profiles suggest no dose adjustments are required based on age and race for COVID-19 drugs, but dose adjustments may be warranted for COVID-19 patients also exhibiting hepatic/renal impairment. PBPK model simulations suggest ELF exposure to attain a target concentration was adequate for most drugs, except for hydroxychloroquine, azithromycin, atazanavir and lopinavir/ritonavir. CONCLUSION We demonstrate that systematically collated data on absorption, distribution, metabolism and excretion, human PK parameters, DDIs and organ impairment can be used to verify simulated plasma and lung tissue exposure for drugs repurposed for COVID-19, justifying broader patient recruitment criteria. In addition, the PBPK model developed was used to study the effect of age and ethnicity on the PK of repurposed drugs, and to assess the correlation between lung exposure and relevant potency values from in vitro studies for SARS-CoV-2.
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Affiliation(s)
- Venkatesh Pilla Reddy
- Modelling & Simulation, Early Oncology, R&D OncologyAstraZenecaCambridgeUK,Clinical Pharmacology and Quantitative Pharmacology, R&D, AstraZenecaCambridgeUK
| | - Eman El‐Khateeb
- Centre for Applied Pharmacokinetic ResearchUniversity of ManchesterManchesterUK,Clinical Pharmacy Department, Faculty of PharmacyTanta UniversityTantaEgypt
| | - Heeseung Jo
- Modelling & Simulation, Early Oncology, R&D OncologyAstraZenecaCambridgeUK
| | | | | | - Shringi Sharma
- Clinical Pharmacology and Quantitative Pharmacology, R&DAstraZenecaUSA
| | - Weifeng Tang
- Clinical Pharmacology and Quantitative Pharmacology, R&DAstraZenecaUSA
| | | | - Amin Rastomi‐Hodjegan
- Centre for Applied Pharmacokinetic ResearchUniversity of ManchesterManchesterUK,Certara UK Limited, Simcyp DivisionSheffieldUK
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21
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Hu S, Lin C, Cai X, Zhu X, Lv F, Nie L, Ji L. The Urinary Glucose Excretion by Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:814074. [PMID: 35154011 PMCID: PMC8830597 DOI: 10.3389/fendo.2021.814074] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/28/2021] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Previous evidence suggested that sodium-glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta-analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function. METHODS We conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes. RESULTS In total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences]. CONCLUSIONS SGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.
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Affiliation(s)
- Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
- *Correspondence: Xiaoling Cai, ; Linong Ji,
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing, China
- *Correspondence: Xiaoling Cai, ; Linong Ji,
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22
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Callegari E, Lin J, Tse S, Goosen TC, Sahasrabudhe V. Physiologically-Based Pharmacokinetic Modeling of the Drug-Drug Interaction of the UGT Substrate Ertugliflozin Following Co-Administration with the UGT Inhibitor Mefenamic Acid. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2020; 10:127-136. [PMID: 33314761 PMCID: PMC7894401 DOI: 10.1002/psp4.12581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 11/12/2020] [Indexed: 01/11/2023]
Abstract
The sodium-glucose cotransporter 2 inhibitor ertugliflozin is metabolized by the uridine 5'-diphospho-glucuronosyltransferase (UGT) isozymes UGT1A9 and UGT2B4/2B7. This analysis evaluated the drug-drug interaction (DDI) following co-administration of ertugliflozin with the UGT inhibitor mefenamic acid (MFA) using physiologically-based pharmacokinetic (PBPK) modeling. The ertugliflozin modeling assumptions and parameters were verified using clinical data from single-dose and multiple-dose studies of ertugliflozin in healthy volunteers, and the PBPK fraction metabolized assignments were consistent with human absorption, distribution, metabolism, and excretion results. The model for MFA was developed using clinical data, and in vivo UGT inhibitory constant values were estimated using the results from a clinical DDI study with MFA and dapagliflozin, a UGT1A9 and UGT2B4/2B7 substrate in the same chemical class as ertugliflozin. Using the verified compound files, PBPK modeling predicted an ertugliflozin ratio of area under the plasma concentration-time curves (AUCR ) of 1.51 when co-administered with MFA. ClinicalTrials.gov identifier: NCT00989079.
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Affiliation(s)
- Ernesto Callegari
- Department of Medicine Design-Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
| | - Jian Lin
- Department of Medicine Design-Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
| | - Susanna Tse
- Department of Medicine Design-Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
| | - Theunis C Goosen
- Department of Medicine Design-Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
| | - Vaishali Sahasrabudhe
- Department of Clinical Pharmacology, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut, USA
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23
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SGLT2 inhibitors, an accomplished development in field of medicinal chemistry: an extensive review. Future Med Chem 2020; 12:1961-1990. [DOI: 10.4155/fmc-2020-0154] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Diabetes is a chronic progressive metabolic disease caused by insulin deficiency or insulin resistance. In spite of the availability of several antihyperglycaemics, there is a need for the development of safer antidiabetic drugs due to their undesirable effects. Sodium-glucose cotransporter-2 inhibitors are a class of antidiabetics, which hinder the reabsorption of glucose in the kidneys, causing excretion of glucose via urine. Sodium-glucose cotransporter-2 inhibitors are a well-tolerated class with no significant adverse effects and are found to be favorable in certain conditions, which may be rudimentary to cardiovascular and renal diseases. The current advancements in their design and development, their mechanism of action, structure–activity relationship, synthesis and in silico development along with their auxiliary roles have been extensively reviewed.
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24
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Milder TY, Stocker SL, Day RO, Greenfield JR. Potential Safety Issues with Use of Sodium-Glucose Cotransporter 2 Inhibitors, Particularly in People with Type 2 Diabetes and Chronic Kidney Disease. Drug Saf 2020; 43:1211-1221. [PMID: 33095409 PMCID: PMC7582030 DOI: 10.1007/s40264-020-01010-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2020] [Indexed: 12/31/2022]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a major advance in the fields of diabetology, nephrology, and cardiology. The cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of their glycaemic effects, and this understanding is central to the use of these agents in the high-risk population of people with type 2 diabetes and chronic kidney disease. There are a number of potential safety issues associated with the use of SGLT2 inhibitors. These include the rare but serious risks of diabetic ketoacidosis and necrotising fasciitis of the perineum. The data regarding a possibly increased risk of lower limb amputation and fracture with SGLT2 inhibitor therapy are conflicting. This article aims to explore the potential safety issues associated with the use of SGLT2 inhibitors, with a particular focus on the safety of these drugs in people with type 2 diabetes and chronic kidney disease. We discuss strategies that clinicians can implement to minimise the risk of adverse effects including diabetic ketoacidosis and volume depletion. Risk mitigation strategies with respect to SGLT2 inhibitor-associated diabetic ketoacidosis are of particular importance during the current coronavirus disease 2019 (COVID-19) pandemic.
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Affiliation(s)
- Tamara Y Milder
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, Australia.,Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Richard O Day
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, Australia.,St. Vincent's Clinical School, University of NSW, Sydney, Australia
| | - Jerry R Greenfield
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, Australia. .,Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, Australia. .,St. Vincent's Clinical School, University of NSW, Sydney, Australia.
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25
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Abstract
The European Society of Cardiology recently addressed the use of SGLT2 inhibitor use in the treatment of heart failure (HF). Dapagliflozin is a SGLT2 inhibitor recently approved by the US FDA for treatment of patients with HF with a reduced ejection fraction with a New York Heart Association classification of II-IV. Dapagliflozin significantly decreases the risk of worsening HF or death from cardiovascular cause compared with placebo and this risk does not differ based on the presence or absence of Type 2 diabetes. This paper aims to summarize the chemistry, pharmacodynamics and pharmacokinetics of dapagliflozin; and evaluates the clinical efficacy of dapagliflozin in the treatment of HF.
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Affiliation(s)
- Sara Sotirakos
- Trinity College Dublin, School of Medicine, Dublin 2, Ireland
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26
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Toyoshima J, Saito M, Kaibara A, Isaka H, Sakatani T. Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients With Type 1 and Type 2 Diabetes Mellitus. Clin Ther 2020; 42:1787-1798.e3. [PMID: 32839028 DOI: 10.1016/j.clinthera.2020.07.009] [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: 04/24/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 11/29/2022]
Abstract
PURPOSE To characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM. METHODS The PK (AUC24h of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (Emax) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM. FINDINGS Data from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC24h of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean Emax and AUC24h producing 50% of Emax (EX50) were 45.1 mL/min (95% CI, 37.0-53.2 mL/min) and 2160 ng·h/mL (95% CI, 929-3390 ng·h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model. IMPLICATIONS The PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. ClinicalTrials.gov identifiers: NCT01023945 and NCT02529449.
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27
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A Phase I Study on the Pharmacokinetics and Pharmacodynamics of DJT1116PG, a Novel Selective Inhibitor of Sodium-glucose Cotransporter Type 2, in Healthy Individuals at Steady State. Clin Ther 2020; 42:892-905.e3. [PMID: 32265061 DOI: 10.1016/j.clinthera.2020.03.007] [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: 12/11/2019] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 11/23/2022]
Abstract
PURPOSE DJT1116PG, which selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter type 2, was developed as an insulin-independent treatment for type 2 diabetes mellitus. This Phase I trial evaluated the pharmacokinetic and pharmacodynamic properties of DJT1116PG at steady state in healthy Chinese individuals. METHODS This was a multiple ascending dose study of DJT1116PG (20, 50, and 100 mg once daily for 7 days) that included 36 healthy individuals. FINDINGS There were no serious adverse events or deaths in these studies, and no adverse event led to study discontinuation. Oral DJT1116PG was rapidly absorbed with a Tmax of 0.75-1.5 h and a t½ of 12-16.2 h. Systemic exposure (Cmax and AUC) of DJT1116PG and its inactive metabolites (T1444, T1454, and T1830) increased in a dose-dependent manner. Urinary glucose excretion (UGE) plateaued at 50 mg of DJT1116PG in a previous single ascending dose study and on day 1 of this study. UGE plateaued at 20 mg of DJT1116PG on day 7 of this study. Serum glucose parameters were similar in individuals who received DJT1116PG or placebo. IMPLICATIONS DJT1116PG was well tolerated in healthy Chinese individuals. At steady state, UGE plateaued at 20 mg of DJT1116PG in these individuals. These findings will inform the selection of doses for further early-stage clinical trials of DJT1116PG. Chinese Drug Trial Identifier: CTR20160986.
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28
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Gu N, Park SI, Chung H, Jin X, Lee S, Kim TE. Possibility of pharmacokinetic drug interaction between a DPP-4 inhibitor and a SGLT2 inhibitor. Transl Clin Pharmacol 2020; 28:17-33. [PMID: 32274378 PMCID: PMC7136081 DOI: 10.12793/tcp.2020.28.e4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 12/23/2022] Open
Abstract
Type 2 diabetes mellitus is a multifactorial condition characterized by high level of sugar in the blood. To control hyperglycemia, combination therapy is recommended if monotherapy fails to achieve glycemic control. The combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium-glucose cotransporter type 2 (SGLT2) inhibitor is a promising option of the combination therapies in terms of safety as well as efficacy. Despite of the value of combination therapy of these two agents, the pharmacokinetic drug interactions between these two classes of agents have been evaluated in a few drugs. Thus, we reviewed the potential pharmacokinetic drug interaction based on the in vitro metabolism- and transporter-mediated drug interaction information as well as drug interaction studies in human, between a DPP-4 inhibitor and a SGLT2 inhibitor which are marketed in South Korea.
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Affiliation(s)
- Namyi Gu
- Department of Clinical Pharmacology and Therapeutics, Clinical Trial Center, Dongguk University College of Medicine and Ilsan Hospital, Goyang, Korea
| | - Sang-In Park
- Department of Pharmacology, College of Medicine, Kangwon National University, Chuncheon, Korea
| | - Hyewon Chung
- Department of Clinical Pharmacology and Toxicology, Korea University Guro Hospital, Seoul, Korea
| | - Xuanyou Jin
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - SeungHwan Lee
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea
| | - Tae-Eun Kim
- Department of Clinical Pharmacology, Konkuk University Medical Center, Seoul, Korea
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29
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Scheen AJ. Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Expert Opin Drug Saf 2020; 19:243-256. [DOI: 10.1080/14740338.2020.1733967] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- André J Scheen
- Division of Clinical Pharmacology, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, Belgium
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège, Belgium
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30
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Zhang H, Zhu X, Li X, Chen H, Wu M, Li C, Liu J, Liu C, Zhang Y, Ding Y. Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium-glucose co-transporter-2, in people with type 2 diabetes mellitus. Diabetes Obes Metab 2020; 22:191-202. [PMID: 31588657 DOI: 10.1111/dom.13887] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 09/18/2019] [Accepted: 09/27/2019] [Indexed: 12/24/2022]
Abstract
AIMS To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of rongliflozin in a cohort of healthy Chinese people and people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS We examined the effects of a single ascending dose (SAD) of rongliflozin (10-200 mg) in combination with food (20 mg) in 50 healthy people, and a multiple ascending dose (MAD) of rongliflozin (10-50 mg once daily for 12 days) in 36 people with T2DM. RESULTS No serious adverse events (AEs) or discontinuations as a result of AEs (related to rongliflozin) occurred in either study. In healthy participants and those with T2DM, rongliflozin was rapidly absorbed, with a time to maximum plasma concentration of 0.63 to 1.75 hours. Systemic exposure (maximum observed serum concentration and area under the curve) to rongliflozin and its inactive major metabolites (T1444, T1454 and T1830) increased in proportion to dose. In the SAD and MAD studies, there was a dose-related increase in urinary glucose excretion (UGE) ranging from 10 to 50 mg rongliflozin. This increase in UGE was associated with dose-related decreases in serum glucose values in people with T2DM in the MAD group. In the SAD group, UGE plateaued at 50 to 200 mg. CONCLUSIONS Rongliflozin was well tolerated in all participants. The PK and PD measurements obtained for rongliflozin demonstrate a dose-response relationship when the drug is administered at doses ranging from 10 to 50 mg in healthy people and in people with T2DM.
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Affiliation(s)
- Hong Zhang
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Xiaoxue Zhu
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Xiaojiao Li
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Hong Chen
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Min Wu
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Cuiyun Li
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Jingrui Liu
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Chengjiao Liu
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
| | - Yingjun Zhang
- State Key Laboratory of Anti-Infective Drug Development, HEC R&D Centre, Sunshine Lake Pharma Co., Ltd, Dongguan, Guangzhou, China
| | - Yanhua Ding
- Phase I Clinical Research Centre, First Hospital of Jilin University, Jilin, China
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Dias BCL, Fachi MM, de Campos ML, Degaut FLD, Peccinini RG, Pontarolo R. A new HPLC-MS/MS method for the simultaneous quantification of SGLT2 inhibitors and metformin in plasma and its application to a pharmacokinetic study in healthy volunteers. Biomed Chromatogr 2019; 33:e4663. [PMID: 31339572 DOI: 10.1002/bmc.4663] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/10/2019] [Accepted: 07/17/2019] [Indexed: 11/06/2022]
Abstract
Monitoring the plasma concentrations of metformin and sodium-glucose cotransporter-2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) is essential for pharmacokinetic and bioequivalence studies and therapeutic monitoring. The present work therefore aimed to develop and validate a high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous quantification of these drugs in human plasma. The analyses were performed using an Agilent 1200 HPLC system coupled to an Applied Biosystems API 3200 triple quadrupole MS/MS with electrospray ionization in positive ion mode. After one-step protein precipitation of plasma with acetonitrile containing 0.1% formic acid, chromatographic separation was achieved on an Xbridge C18 column, with a mobile phase consisting of a gradient of water and acetonitrile, both containing 1 mm ammonium formate and 0.1% formic acid. Quantification was performed in multiple reaction monitoring mode using m/z 130.1 → 71.1 for metformin, m/z 462.0 → 191.2 for canagliflozin, m/z 426.1 → 167.1 for dapagliflozin and m/z 468.0 → 354.9 for empagliflozin. The proposed method was validated and demonstrated to be adequate for the quantification of metformin, canagliflozin, dapagliflozin and empagliflozin for clinical monitoring, pharmacokinetics and bioequivalence studies.
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Affiliation(s)
| | | | | | | | - Rosângela Gonçalves Peccinini
- Department of Natural Active Principles and Toxicology, São Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara, Brazil
| | - Roberto Pontarolo
- Department of Pharmacy, Federal University of Parana, Curitiba, Paraná, Brazil
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Milder TY, Stocker SL, Samocha-Bonet D, Day RO, Greenfield JR. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes-cardiovascular and renal benefits in patients with chronic kidney disease. Eur J Clin Pharmacol 2019; 75:1481-1490. [PMID: 31377891 DOI: 10.1007/s00228-019-02732-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Sodium-glucose cotransporter 2 (SGLT2) inhibitors have important cardiovascular and renal benefits in adults with type 2 diabetes who have or are at high risk of cardiovascular and renal disease. These benefits are seen in patients with impaired renal function where the glucose-lowering effects are not observed. Here, we review the pharmacokinetics and pharmacology of SGLT2 inhibitors in relation to cardiovascular and renal outcomes in patients with chronic kidney disease (CKD). METHODS We searched PubMed and EMBASE for original research, meta-analyses and review articles relevant to the pharmacokinetics, and cardiac and renal outcomes of SGLT2 inhibitors published up until June 2019. Specialist society guidelines and publications were also consulted. RESULTS Renal impairment is currently a contraindication to SGLT2 inhibitor use largely due to limited anti-hyperglycaemic efficacy. However, in cardiovascular outcome trials, and a dedicated renal outcome trial, cardiovascular and renal benefits were seen in participants with CKD suggesting that mechanisms underlying the cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of the glucose-lowering action of these agents. CONCLUSIONS Despite minimal glycaemic benefits in patients with type 2 diabetes and stage 3 CKD, the cardiovascular and renal benefits of these agents are preserved in this group of patients. Whether these agents have cardiovascular and renal benefits in patients with stage 4 CKD and patients with non-diabetic CKD needs further research.
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Affiliation(s)
- Tamara Y Milder
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, NSW, Australia
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
- St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
- Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
- St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
| | - Dorit Samocha-Bonet
- St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
- Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Richard O Day
- Department of Clinical Pharmacology and Toxicology, St. Vincent's Hospital, Sydney, NSW, Australia
- St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia
| | - Jerry R Greenfield
- Department of Diabetes and Endocrinology, St. Vincent's Hospital, Sydney, NSW, Australia.
- St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia.
- Diabetes and Metabolism, Garvan Institute of Medical Research, Sydney, NSW, Australia.
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33
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Galli M, D'Amario D, Sofia C, Vaccarella M, Crea F, Aspromonte N. Clinical potential relevance of metabolic properties of SGLT2 inhibitors in patients with heart failure. Expert Opin Drug Metab Toxicol 2018; 14:1273-1285. [PMID: 30472914 DOI: 10.1080/17425255.2018.1551360] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction: Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2DM) contributes significantly to end-organ damage and HF-related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2DM. Recently, a novel class of antidiabetic drugs has been introduced: sodium glucose co-trasport-2 inhibitors (SGLT2i). Initially designed for patients with T2DM to reduce kidney blood glucose resorption, SGLT2i rapidly gained attention among HF specialists since they were able to show a beneficial prognostic impact in patients affected by HF and T2DM, even independently from the glycemic control as suggested by the EMPA-REG OUTCOME and CANVAS trials. Areas covered: The present review focuses on the mechanisms and the current clinical evidence supporting the use of SGLT2i in HF patients with T2DM. Moreover, the SGLT2i pharmacokinetic and pharmacodynamic properties will be presented in order to better understand the rationale and the design of the ongoing clinical trials investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. Expert opinion: SGLT2i are emerging as an effective and safe therapy for the treatment of T2DM and current evidence has unexpectedly demonstrated a robust cardiovascular protection in HF patients with T2DM. Therefore, ongoing clinical trials are investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. However, it is methodologically disappointing that the mechanisms underlying the encouraging results in cardiovascular protection of this drug class are still not fully understood. A better understanding of the pharmacokinetic and pharmacodynamic properties of SGLT2i is necessary in order to better determine the effect of this new class of drugs in patients with HF.
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Affiliation(s)
- Mattia Galli
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Domenico D'Amario
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Carmelo Sofia
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Marcello Vaccarella
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Filippo Crea
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
| | - Nadia Aspromonte
- a Department of Cardiovascular and Thoracic Sciences , Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore , Rome , Italy
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Lv X, Zhang JB, Hou J, Dou TY, Ge GB, Hu WZ, Yang L. Chemical Probes for Human UDP-Glucuronosyltransferases: A Comprehensive Review. Biotechnol J 2018; 14:e1800002. [PMID: 30192065 DOI: 10.1002/biot.201800002] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/19/2018] [Indexed: 01/11/2023]
Abstract
UGTs play crucial roles in the metabolism and detoxification of both endogenous and xenobiotic compounds. The key roles of UGTs in human health have garnered great interest in the design and development of specific probes for human UGTs. However, in contrast to other human enzymes, the probe substrates for human UGTs are rarely reported, owing to the highly overlapping substrate specificities of UGTs and the lack of the integrated crystal structures of UGTs. Over the past decades, many efforts are made to develop specific probe substrates for UGTs and use them in both basic research and drug discovery. This review focuses on recent progress in the development of probe substrates for UGTs and their biomedical applications. A long list of chemical probes for UGTs, including non-fluorescent and fluorescent probes along with their structural information and kinetic parameters, are prepared and analyzed. Additionally, challenges and future directions in this field are highlighted in the final section. All information and knowledge presented in this review provide practical tools/methods for measuring UGT activities in complex biological samples, which will be very helpful for rapid screening and characterization of UGT modulators, and for exploring the relevance of UGT enzymes to human diseases.
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Affiliation(s)
- Xia Lv
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, College of Life Science, Dalian Minzu University, Dalian, 116600, China.,Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | | | - Jie Hou
- Dalian Medical University, Dalian, 116044, China
| | - Tong-Yi Dou
- School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, China
| | - Guang-Bo Ge
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wen-Zhong Hu
- Key Laboratory of Biotechnology and Bioresources Utilization, Ministry of Education, College of Life Science, Dalian Minzu University, Dalian, 116600, China
| | - Ling Yang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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35
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Follman KE, Dave RA, Morris ME. Effects of renal impairment on transporter-mediated renal reabsorption of drugs and renal drug-drug interactions: A simulation-based study. Biopharm Drug Dispos 2018; 39:218-231. [PMID: 29635775 DOI: 10.1002/bdd.2128] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 02/13/2018] [Accepted: 03/12/2018] [Indexed: 02/05/2023]
Abstract
Renal impairment (RI) significantly impacts the clearance of drugs through changes in the glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to evaluate quantitatively the effects of renal impairment on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. A previously published semi-mechanistic kidney model incorporating physiologically relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) was utilized in this study. The probe drug/transporter pair utilized was γ-hydroxybutyric acid (GHB) and monocarboxylate transporter 1 (SCL16A1, MCT1). γ-Hydroxybutyric acid concentrations in the blood and amount excreted into urine were simulated using ADAPT 5 for the i.v. dose range of 200-1500 mg/kg in rats and the impact of renal impairment on CLR and AUC was evaluated. A 90% decrease in GFR resulted in a > 100-fold decrease in GHB CLR . When expression of reabsorptive transporters was decreased and fu was increased, CLR approached GFR. The effect of renal impairment on CLR was reduced when the expression of drug metabolizing enzymes (DME) was increased as a result of increased metabolic clearance; the converse held true when the DME expression was decreased. In conclusion, this study quantitatively demonstrated that the effects of renal insufficiency on the clearance of drugs is modulated by transporter expression, contribution of renal clearance to overall clearance, expression of drug metabolizing enzymes, fraction unbound and drug-drug interactions with inhibitors of renal transporters that may be increased in the presence of renal impairment.
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Affiliation(s)
- Kristin E Follman
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
| | - Rutwij A Dave
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
| | - Marilyn E Morris
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA
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36
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Chen F, Li DY, Zhang B, Sun JY, Sun F, Ji X, Qiu JC, Parker RB, Laizure SC, Xu J. Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance? Drug Metab Rev 2018; 50:369-397. [PMID: 30221555 DOI: 10.1080/03602532.2018.1497645] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Feng Chen
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - De-Yi Li
- School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Bo Zhang
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jie-Yu Sun
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Fang Sun
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Xing Ji
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jin-Chun Qiu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Robert B. Parker
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - S. Casey Laizure
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Jing Xu
- Department of Pharmacy, Children's Hospital of Nanjing Medical University, Nanjing, China
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37
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Smith WB, Hall J, Berg JK, Kazimir M, Yamamoto A, Walker S, Lee CA, Shen Z, Wilson DM, Zhou D, Gillen M, Marbury TC. Effect of Renal Impairment on the Pharmacokinetics and Pharmacodynamics of Verinurad, a Selective Uric Acid Reabsorption Inhibitor. Clin Drug Investig 2018; 38:703-713. [PMID: 29949102 PMCID: PMC6061379 DOI: 10.1007/s40261-018-0652-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
BACKGROUND AND OBJECTIVE: Verinurad (RDEA3170) is a high-affinity, selective URAT1 transporter inhibitor in development for treating gout and asymptomatic hyperuricemia. This Phase I, single-dose study investigated the pharmacokinetics, pharmacodynamics, and safety of verinurad in adults with renal impairment and controls with normal renal function. METHODS Males aged 18-85 years were enrolled with serum urate (sUA) 4.5-10 mg/dl and creatinine clearance 60- < 90, 30- < 60, 15- < 30, or ≥ 90 ml/min (mild, moderate, severe renal impairment and controls, respectively; n = 7/8). Verinurad 15 mg was administered orally under fasted conditions. Serial plasma/serum and urine samplings were 30 min pre-dose to 72 h post-dose. RESULTS Compared to controls, verinurad maximum observed plasma concentration increased by 53, 73, and 128% and area under the concentration-time curve increased by 24, 148, and 130%, in subjects with mild, moderate, and severe renal impairment, respectively; renal clearance decreased by 5, 42, and 79%. Exposures of major verinurad metabolites also increased with increasing renal impairment. Verinurad decreased sUA in all groups, with greater maximal changes in control and mild renal impairment than moderate and severe impairment groups (- 38.3, - 36.9, - 20.5, - 12.6%, respectively). There were no adverse event-related withdrawals or clinically meaningful changes in laboratory values. CONCLUSION Exposures of verinurad and metabolites increased with decreasing renal function. Consistent with the renal-dependent mechanism of action of verinurad, increasing severity of renal impairment was associated with decreased sUA lowering. Verinurad safety assessments were similar regardless of renal impairment. Continued investigation of verinurad is warranted in patients with gout and renal impairment. CLINICALTRIALS. GOV IDENTIFIER NCT02219516.
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Affiliation(s)
- William B Smith
- Volunteer Research Group, University of TN Medical Center, 1928 Alcoa Highway, Suite 107, Knoxville, TN, 37920, USA.
| | - Jesse Hall
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Jolene K Berg
- DaVita Clinical Research, 825 S. 8th Street, Suite 300, Minneapolis, MN, 55404, USA
| | - Michal Kazimir
- DaVita Clinical Research, Medical Plaza 1, 11750 West 2nd Place, Suite 300, Lakewood, CO, 80228, USA
| | - Amy Yamamoto
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Susan Walker
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Caroline A Lee
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Zancong Shen
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - David M Wilson
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Dongmei Zhou
- Ardea Biosciences, Inc, 9390 Towne Centre Drive, San Diego, CA, 92121, USA
| | - Michael Gillen
- AstraZeneca Pharmaceuticals LP, 1 Medimmune Way, Gaithersburg, MD, 20878, USA
| | - Thomas C Marbury
- Orlando Clinical Research Center, 5055 South Orange Ave, Orlando, FL, 32809-3017, USA
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38
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Hallow KM, Greasley PJ, Helmlinger G, Chu L, Heerspink HJ, Boulton DW. Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data. Am J Physiol Renal Physiol 2018; 315:F1295-F1306. [PMID: 30019930 DOI: 10.1152/ajprenal.00202.2018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The mechanisms of cardiovascular and renal protection observed in clinical trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg of dapagliflozin once daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiological variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na+/H+ exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower glomerular filtration rate, suggesting that cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.
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Affiliation(s)
- K Melissa Hallow
- School of Chemical, Materials, and Biomedical Engineering, University of Georgia , Athens, Georgia.,Department of Epidemiology and Biostatistics, University of Georgia , Athens, Georgia
| | - Peter J Greasley
- Early Clinical Development, Innovative Medicines, AstraZeneca, Gothenburg , Sweden
| | - Gabriel Helmlinger
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, Waltham, Massachusetts
| | - Lulu Chu
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, Waltham, Massachusetts
| | - Hiddo J Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands
| | - David W Boulton
- Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, Gaithersburg, Maryland
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39
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Samukawa Y, Haneda M, Seino Y, Sasaki T, Fukatsu A, Kubo Y, Sato Y, Sakai S. Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment. Clin Pharmacol Drug Dev 2018; 7:820-828. [PMID: 29693800 PMCID: PMC6220780 DOI: 10.1002/cpdd.456] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 02/06/2018] [Indexed: 11/15/2022]
Abstract
This open‐label, parallel‐group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5‐mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60–89, 45–59, 30–44, 15–29 mL/min/1.73 m2, respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment.
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Affiliation(s)
| | - Masakazu Haneda
- Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Hokkaido, Japan
| | | | - Takashi Sasaki
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Chiba, Japan
| | | | - Yusuke Kubo
- Taisho Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yuri Sato
- Taisho Pharmaceutical Co., Ltd., Tokyo, Japan
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40
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Abstract
In 2017, the FDA approved several new drugs for use in primary care. This article highlights the following new drugs: brodalumab (Siliq), dapagliflozin and saxagliptin (Qtern), dupilumab (Dupixent), oxymetazoline (Rhofade), safinamide (Xadago), and sarilumab (Kevzara).
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Affiliation(s)
- Geoffrey Mospan
- Geoffrey Mospan is an assistant professor of pharmacy at Wingate University School of Pharmacy, Wingate, N.C. Cortney Mospan is an assistant professor of pharmacy at Wingate University School of Pharmacy, Wingate, N.C. Shayna Vance is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C. Alyssa Bradshaw is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C. Kalyn Meosky is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C. Kirklin Bowles is a 4th year PharmD candidate at Wingate University School of Pharmacy, Wingate, N.C
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41
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Di Lullo L, Mangano M, Ronco C, Barbera V, De Pascalis A, Bellasi A, Russo D, Di Iorio B, Cozzolino M. The treatment of type 2 diabetes mellitus in patients with chronic kidney disease: What to expect from new oral hypoglycemic agents. Diabetes Metab Syndr 2017; 11 Suppl 1:S295-S305. [PMID: 28292575 DOI: 10.1016/j.dsx.2017.03.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 03/03/2017] [Indexed: 02/06/2023]
Abstract
Worldwide, an estimated 200 million people have chronic kidney disease (CKD), whose most common causes include hypertension, arteriosclerosis, and diabetes. About 40% of patients with diabetes develop CKD and intensive blood glucose control through pharmacological intervention can delay CKD progression. Standard therapies for the treatment of type 2 diabetes mellitus include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2-5) and without dose adjustment. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment.
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Affiliation(s)
- Luca Di Lullo
- Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy.
| | - Michela Mangano
- Department of Health Sciences, S. Paolo Hospital, University of Milan, Italy
| | - Claudio Ronco
- International Renal Research Institute, S. Bortolo Hospital, Vicenza, Italy
| | - Vincenzo Barbera
- Department of Nephrology and Dialysis, L. Parodi - Delfino Hospital, Colleferro, Italy
| | | | - Antonio Bellasi
- Department of Nephrology and Dialysis, ASST Lariana, S. Anna Hospital, Como, Italy
| | - Domenico Russo
- Clinical Nephrology, University Federico II°, Naples, Italy
| | - Biagio Di Iorio
- Department of Nephrology and Dialysis, Landolfi Hospital, Solofra, Italy
| | - Mario Cozzolino
- Department of Health Sciences, S. Paolo Hospital, University of Milan, Italy
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Okada J, Matsumoto S, Kaira K, Saito T, Yamada E, Yokoo H, Katoh R, Kusano M, Okada S, Yamada M. Sodium Glucose Cotransporter 2 Inhibition Combined With Cetuximab Significantly Reduced Tumor Size and Carcinoembryonic Antigen Level in Colon Cancer Metastatic to Liver. Clin Colorectal Cancer 2017; 17:e45-e48. [PMID: 29054804 DOI: 10.1016/j.clcc.2017.09.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 07/31/2017] [Accepted: 09/20/2017] [Indexed: 01/09/2023]
Affiliation(s)
- Junichi Okada
- Department of Internal Medicine, Gunmaken Saiekikai Maebashi Hospital, Maebashi, Japan; Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Shunichi Matsumoto
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Kyoichi Kaira
- Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Tsugumichi Saito
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Eijiro Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideaki Yokoo
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ryuji Katoh
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Motoyasu Kusano
- Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, Maebashi, Japan
| | - Shuichi Okada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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Lioudaki E, Whyte M, Androulakis ES, Stylianou KG, Daphnis EK, Ganotakis ES. Renal Effects of SGLT-2 Inhibitors and Other Anti-diabetic Drugs: Clinical Relevance and Potential Risks. Clin Pharmacol Ther 2017; 102:470-480. [DOI: 10.1002/cpt.731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 04/28/2017] [Accepted: 05/02/2017] [Indexed: 12/11/2022]
Affiliation(s)
- E Lioudaki
- Renal Unit; Epsom and St Helier University Hospitals NHS Trust; London UK
- Department of Nephrology; University Hospital of Heraklion; Greece
| | - M Whyte
- Department of Clinical & Experimental Medicine; University of Surrey; Department of Medicine King's College Hospital
| | - ES Androulakis
- Cardiology Department; St George's University Hospital NHS; London UK
| | - KG Stylianou
- Department of Nephrology; University Hospital of Heraklion; Greece
| | - EK Daphnis
- Department of Nephrology; University Hospital of Heraklion; Greece
| | - ES Ganotakis
- Department of Internal Medicine; University Hospital of Heraklion; Greece
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Lacava V, Pellicanò V, Ferrajolo C, Cernaro V, Visconti L, Conti G, Buemi M, Santoro D. Novel avenues for treating diabetic nephropathy: new investigational drugs. Expert Opin Investig Drugs 2017; 26:445-462. [PMID: 28277032 DOI: 10.1080/13543784.2017.1293039] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 02/06/2017] [Indexed: 01/01/2023]
Abstract
At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed. Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD. Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further studies with a greater number of patients will establish a better approach for diabetic nephropathy.
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Affiliation(s)
- Viviana Lacava
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Vincenzo Pellicanò
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Carmen Ferrajolo
- b Department of Experimental Medicine , Second University of Naples , Napoli , Italy
| | - Valeria Cernaro
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Luca Visconti
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Giovanni Conti
- c Unit of Pediatric Nephrology and Rheumatology , University of Messina , Messina , Italy
| | - Michele Buemi
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
| | - Domenico Santoro
- a Unit of Nephrology and Dialysis , University of Messina , Messina , Italy
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Janus N, Launay-Vacher V. Pharmacokinetic/pharmacodynamic considerations for cancer patients undergoing hemodialysis. Expert Opin Drug Metab Toxicol 2017; 13:617-623. [PMID: 28537215 DOI: 10.1080/17425255.2017.1292252] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION The increased incidence of cancer in hemodialysis patients has been discussed since the mid-70s. Today, physicians regularly encounter situations where they must manage the prescription of anticancer drugs in hemodialysis patients. Areas covered: Hemodialysis patients are at risk of dose-related toxicities due to pharmacokinetic modifications. Hemodialysis patients are at risk of therapeutic drug removal during their hemodialysis session, which may result in a loss of efficacy. In the advent of novel immunotherapies, particularly tumor vaccines, there is an increased theoretical risk of pharmacodynamic modification. Indeed, pharmacodynamic modifications have already been reported for viral vaccines. Expert opinion: It is important to consider all of the potential pharmacokinetic/pharmacodynamic modifications before prescribing anticancer drugs in hemodialysis patients. However, pharmacokinetic/pharmacodynamic modification should not be considered a contraindication for anticancer drug use in hemodialysis patients, rather, clinicians should be aware of the need individualize treatment according to available recommendations.
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Affiliation(s)
- Nicolas Janus
- a Service ICAR, Pitié-Salpêtrière Hospital , Paris , France.,b Nephrology Department , Pitié-Salpêtrière Hospital , Paris , France
| | - Vincent Launay-Vacher
- a Service ICAR, Pitié-Salpêtrière Hospital , Paris , France.,b Nephrology Department , Pitié-Salpêtrière Hospital , Paris , France
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Abstract
Blood glucose-lowering treatment options generally target insulin action or beta-cell function. In diabetes, expression of the sodium-glucose cotransporter-2 (SGLT2) genes is up-regulated and renal threshold increased, resulting in increased glucose reabsorption from glomerular filtrate, reducing urinary glucose excretion and worsening the hyperglycemic condition. The SGLT2 inhibitors (SGLT2i) are a novel class of anti-diabetic drugs that lower blood glucose levels through the suppression of renal glucose reabsorption thereby promoting renal glucose excretion. The efficacy of SGLT2i is reduced in renal impairment because the ability of glucose-lowering is directly proportional to glomerular filtration rate. On the other hand, ongoing research suggests that SGLT2i may offer potential nephroprotection in diabetes. The SGLT2i have been shown to reduce glomerular hyperfiltration, systemic and intraglomerular pressure and the biochemical progression of chronic kidney disease. Additional mechanisms through which SGLT2i exert nephroprotection may include normalizing blood pressure and uricemia. This review explores this bidirectional relationship of the SGLT2i and the glomerulus. While SGLT2i exhibit reduced efficacy in later stages, they exhibit nephroprotective effects in early stages of renal impairment. Funding: Janssen India (Pharmaceutical division of Johnson & Johnson).
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Pafili K, Maltezos E, Papanas N. The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes. Expert Opin Investig Drugs 2016; 25:1133-52. [DOI: 10.1080/13543784.2016.1216970] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Vakkalagadda B, Lubin S, Reynolds L, Liang D, Marion AS, LaCreta F, Boulton DW. Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study. Clin Ther 2016; 38:1890-9. [PMID: 27491280 DOI: 10.1016/j.clinthera.2016.07.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 07/07/2016] [Accepted: 07/08/2016] [Indexed: 11/24/2022]
Abstract
PURPOSE This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug-drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered. METHODS Healthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of ≥6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for Cmax and AUCinf were within 0.80 to 1.25. FINDINGS The results indicated that dapagliflozin had no effect on the pharmacokinetic properties of saxagliptin, 5-OH saxagliptin, or saxagliptin total active moiety and vice versa. The 90% CIs for Cmax and AUCinf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. IMPLICATIONS These data indicate that coadministration of saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999.
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Affiliation(s)
| | | | | | - Dan Liang
- ICON Development Solutions, LLC, Hanover, Maryland
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Parkinson J, Tang W, Johansson CC, Boulton DW, Hamrén B. Comparison of the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus. Diabetes Obes Metab 2016; 18:685-92. [PMID: 27299483 DOI: 10.1111/dom.12647] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 12/31/2015] [Accepted: 02/11/2016] [Indexed: 12/19/2022]
Abstract
AIMS To quantitatively compare the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus (T2DM) and to assess the potential impact of covariate effects. METHODS Data from three clinical studies of single-dose (2.5, 5 and 10 mg), orally administered dapagliflozin in adult (NCT00162305, NCT00538174) and paediatric (NCT01525238) patients with T2DM were analysed to examine the relationship between dapagliflozin exposure (area under concentration-time curve) and response [24-h urinary glucose excretion (UGE)] using a sigmoidal maximum effect model. Baseline fasting plasma glucose (FPG), estimated glomerular filtration rate (eGFR), baseline 24-h UGE, sex and race were evaluated as covariates. RESULTS Data from 63 predominantly white or Asian (92.4%) adult and 20 paediatric (45.8% white; 45.8% black) patients were included. The model appeared robust, with predictions fitting well with observed data. Baseline eGFR, FPG and sex were significant covariates in both populations; race was a significant covariate in the paediatric population only. Model-predicted UGE response was higher in paediatric (47.4, 67.5 and 85.9 g/24 h for 2.5, 5 and 10 mg) than in adult (31.2, 43.5 and 54.3 g/24 h for 2.5, 5 and 10 mg) patients, which may be associated with the higher eGFR values in paediatric patients. CONCLUSIONS After a single oral dose of dapagliflozin, adult and paediatric patients with T2DM had similar exposure-response relationships after accounting for significant covariates. These results support the planned dosage strategy for a phase III dapagliflozin safety and efficacy study in paediatric patients with T2DM, for whom treatment options are currently limited.
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Affiliation(s)
| | - W Tang
- AstraZeneca, Gaithersburg, MD, USA
| | | | | | - B Hamrén
- AstraZeneca Gothenburg, Mölndal, Sweden
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Davies M, Chatterjee S, Khunti K. The treatment of type 2 diabetes in the presence of renal impairment: what we should know about newer therapies. Clin Pharmacol 2016; 8:61-81. [PMID: 27382338 PMCID: PMC4922775 DOI: 10.2147/cpaa.s82008] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Worldwide, an estimated 200 million people have chronic kidney disease (CKD), the most common causes of which include hypertension, arteriosclerosis, and diabetes. Importantly, ~40% of patients with diabetes develop CKD, yet evidence from major multicenter randomized controlled trials shows that intensive blood glucose control through pharmacological intervention can reduce the incidence and progression of CKD. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2–5) and without dose adjustment; there are contraindications and dose adjustments required for the remaining standard therapies. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment. Notably, reductions in albuminuria, a marker of CKD, are observed with many of the drug classes. Dipeptidyl peptidase-IV inhibitors can be used in all stages of renal impairment, with appropriate dose reduction, with the exception of linagliptin, which can be used without dose adjustment. No dose adjustment is required for liraglutide, albiglutide, and dulaglutide in CKD stages 2 and 3, although all glucagon-like peptide-1 receptor agonists are currently contraindicated in stages 4 and 5 CKD. At stage 3 CKD or greater, the sodium-glucose cotransporter-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) either require dose adjustment or are contraindicated. Ongoing trials, such as CARMELINA, MARLINA, CREDENCE, and CANVAS-R, will help determine the position of these new therapy classes and if they have renoprotective effects in patients with CKD.
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Affiliation(s)
- Melanie Davies
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Sudesna Chatterjee
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester; Leicester Diabetes Centre, University Hospitals of Leicester NHS Trust, Leicester, UK
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