PMID- 37442656 OWN - NLM STAT- MEDLINE DCOM- 20230924 LR - 20230924 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 45 IP - 8 DP - 2023 Aug TI - Pharmacokinetic Variables of Dapagliflozin/Metformin Extended-release Fixed-dose Combination in Healthy Chinese Volunteers and Regional Comparison. PG - 762-769 LID - S0149-2918(23)00216-3 [pii] LID - 10.1016/j.clinthera.2023.06.012 [doi] AB - PURPOSE: A fixed-dose combination (FDC) product combining dapagliflozin and metformin may increase medication adherence in patients with type 2 diabetes mellitus (T2DM) by minimizing pill burden associated with co-administration of individual component (IC) formulations and, consequently, improve cost-efficiency and compliance. This study evaluated the bioequivalence of the dapagliflozin/metformin FDC product versus IC administration in healthy volunteers from a Chinese population and assessed the safety profile of the FDC product. In addition, pharmacokinetic (PK) and safety comparisons of dapagliflozin and metformin across different regions were conducted to evaluate regional differences. METHODS: This single-center, open-label, parallel-cohort, randomized, 2-period, crossover study enrolled Chinese adults (aged 18-55 years). Volunteers in cohort 1 received either a single FDC tablet of dapagliflozin/metformin extended release (XR) (5/500 mg) or IC tablets (dapagliflozin [5 mg] and metformin XR [500 mg]). Volunteers in cohort 2 received a higher dosage in a similar manner (dapagliflozin [10 mg] and metformin XR [1000 mg]). Volunteers in each cohort were subsequently crossed over to receive the alternate cohort treatment. Plasma concentrations of dapagliflozin and metformin were determined, and bioequivalence analyses were performed under standard fed conditions. FINDINGS: Eighty healthy Chinese volunteers (89.9% male; mean age, 28.7 years) were randomized into cohort 1 (n = 40) and cohort 2 (n = 39; 1 volunteer withdrew before receiving study treatment). The mean plasma concentration-time profiles of the dapagliflozin and metformin FDC and IC formulations for both doses were found to be nearly superimposable. Dapagliflozin and metformin XR FDC were bioequivalent to the IC tablets, with 90% CIs for each pairwise comparison contained within the 80% to 125% bioequivalence limits. Both the FDC and IC formulations were well tolerated, with no serious adverse events/death. PK parameters for dapagliflozin in the Chinese volunteers were slightly to moderately higher than those from studies conducted in Brazil, Russia, and the United States, and the safety profile of the dapagliflozin/metformin FDC product was consistent with that of other studies. The difference in PK parameters among the 4 regions was not clinically meaningful. IMPLICATIONS: The bioequivalence of the dapagliflozin/metformin FDC and IC formulations in healthy Chinese adults was established without any new safety concerns. Notably, the observed bioequivalence may be extrapolated to patients with T2DM as the PK parameters of dapagliflozin and metformin in healthy adults are similar to those reported in patients with T2DM. CLINICALTRIALS: gov identifier: NCT04856007. CI - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Zhao, Xiaoying AU - Zhao X AD - Clinical Pharmacology, Development Science, R&D China, AstraZeneca, Shanghai, China. FAU - Ning, Rui AU - Ning R AD - CVRM & Safety, Clinical Science, R&D China, AstraZeneca, Shanghai, China. FAU - Hui, Andrew AU - Hui A AD - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA. FAU - Boulton, David W AU - Boulton DW AD - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA. FAU - Tang, Weifeng AU - Tang W AD - Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA. Electronic address: weifeng.tang@astrazeneca.com. LA - eng SI - ClinicalTrials.gov/NCT04856007 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230711 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 1ULL0QJ8UC (dapagliflozin) RN - 0 (Delayed-Action Preparations) RN - 0 (Drug Combinations) RN - 0 (Hypoglycemic Agents) RN - 9100L32L2N (Metformin) RN - 0 (Tablets) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) SB - IM MH - Adult MH - Female MH - Humans MH - Male MH - Area Under Curve MH - Cross-Over Studies MH - Delayed-Action Preparations/pharmacokinetics/therapeutic use MH - *Diabetes Mellitus, Type 2/drug therapy MH - Drug Combinations MH - East Asian People MH - Healthy Volunteers MH - *Hypoglycemic Agents/pharmacokinetics/therapeutic use MH - *Metformin/pharmacokinetics/therapeutic use MH - Tablets MH - Therapeutic Equivalency MH - *Sodium-Glucose Transporter 2 Inhibitors/pharmacokinetics/therapeutic use OTO - NOTNLM OT - Bioequivalence OT - China OT - Dapagliflozin OT - Fixed-dose combination OT - Metformin OT - Regional comparisons COIS- Declaration of Competing Interest Ms. Zhao, Dr Ning, Mr. Hui, Dr Boulton and Dr Tang are employees of AstraZeneca. Dr Bouton and Dr Tang own AstraZeneca stock and/or stock options. Mr. Hui was a summer intern at AstraZeneca when conducting this research. EDAT- 2023/07/14 13:07 MHDA- 2023/09/04 06:42 CRDT- 2023/07/13 21:57 PHST- 2023/01/27 00:00 [received] PHST- 2023/05/12 00:00 [revised] PHST- 2023/06/12 00:00 [accepted] PHST- 2023/09/04 06:42 [medline] PHST- 2023/07/14 13:07 [pubmed] PHST- 2023/07/13 21:57 [entrez] AID - S0149-2918(23)00216-3 [pii] AID - 10.1016/j.clinthera.2023.06.012 [doi] PST - ppublish SO - Clin Ther. 2023 Aug;45(8):762-769. doi: 10.1016/j.clinthera.2023.06.012. Epub 2023 Jul 11.