Bioequivalence Study to Compare Metformin / Vildagliptin Versus Galvumet®

Overview

The aim of this study is to assess bioequivalence between a single oral dose from the test product Metformin / Vildagliptin tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Pharmaceutical Arab Industries Society, Tunisia versus the reference product Galvumet® tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Novartis. This study also aims to monitor the safety of the subjects. This study is an open label, randomized, fed, single oral dose, two-treatment, two-sequence, and two-period crossover study with a washout interval of at least one week between dosing. Eighteen (18) Tunisian subjects will be enrolled for this study. Subjects will be healthy volunteers, adults, aged between eighteen to fifty (18-50) years, (both inclusive), within the accepted limits for body height \& weight and meeting the selection criteria for this study.

The aim of this study is to assess bioequivalence between a single oral dose from the test product Metformin / Vildagliptin tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Pharmaceutical Arab Industries Society, Tunisia versus the reference product Galvumet® tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Novartis. This study also aims to monitor the safety of the subjects. This study is an open label, randomized, fed, single oral dose, two-treatment, two-sequence, and two-period crossover study with a washout interval of at least one week between dosing. Eighteen (18) Tunisian subjects will be enrolled for this study. Subjects will be healthy volunteers, adults, aged between eighteen to fifty (18-50) years, (both inclusive), within the accepted limits for body height \& weight and meeting the selection criteria for this study. Products under investigation for this study: Test Product: Metformin / Vildagliptin tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Pharmaceutical Arab Industries Society, Tunisia. Reference Product: Galvumet® tablets (1000 mg as metformin hydrochloride / 50 mg as vildagliptin) manufactured by Novartis. Metformin and vildagliptin are two oral antidiabetic drugs. Metformin belongs to biguanide class. Vildagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4). Metformin and vildagliptin are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type two diabetes mellitus. This study will be conducted according to the principles of Good Clinical Practice (GCP) that have their origins in the Declaration of Helsinki. This study will be subject to the review and approval of Persons Protection Committee and of Pharmacy and Medicine Department. Subjects will not be recruited without obtaining their informed consent. Subjects will be covered for adverse events through an insurance company. Subjects will be housed in each study period at least 12 hours before dose administration and until 36 hours after dosing. Subjects will be in a sitting position on chairs for the first 4 hours that follow the dose. After an overnight fast of ten to twelve (10-12) hours and in the morning of the second day of each study period (day 2), a standard high-fat breakfast (800-1000 calories) will be served to subjects, thirteen (30) minutes before dosing. At 08:00 am, the study products will be administered orally in a randomized fashion with 240 ± 2 mL warm 20% glucose solution. During each period of the study, 21 blood samples of 7 mL each will be collected (via an indwelling cannula into lithium heparin tubes) according to the following schedule: Pre dosing (zero time) and 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.5, 3.00, 3.50, 4.00, 4.5, 5.00, 6.00, 7.00, 8.00, 10.00, 12.00, 14.00, 24.00 \& 36.00 hours post dosing. After collection, the blood samples will be placed in an ice bath or other chilling device until centrifugation. Before each period of the study, 21 mL blood sample will be collected for bio-analytical purposes. A blood sample of 3 mL may be needed for a possible control. Samples will be centrifuged at 4000 round per minute for 5 minutes at 10°C. Supernatant plasma will be transferred to pre-labeled polypropylene Eppendorf tubes and stored in freezers at nominal temperature of -20 C unless otherwise advised by the stability studies on samples. Samples from all subjects will be analyzed at the bio-analytical site of the National Center of Pharmacovigilance according to validated in-house procedure using validated Liquid Chromatography-Mass Spectrometry Tandem method for the plasma concentrations of metformin \& vildagliptin. Primary end points would be obtaining the following pharmacokinetic parameters for metformin \& vildagliptin: Cmax, Air Under Cover (AUC) 0 - t \& AUC 0 - ∞. Secondary end points would be obtaining the following pharmacokinetic parameters for metformin \& vildagliptin: Tmax, T half \& K elimination (λz). Statistical analysis of primary endpoints will include descriptive statistics, Analysis of Variance (ANOVA), and Confidence Interval (CI). The average bioequivalence of the products is concluded if the two-sided 90 % CI for the test to reference ratio of the population means is within 80.00 - 125.00 % for each of the Ln-transformed data of the following primary end points for metformin \& vildagliptin: Cmax, AUC 0 - t \& AUC 0 - ∞ and if there were no safety concerns and both products were well tolerated by the study subjects.