Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg Relative to Originator

Overview

The study is to compare the rate and extent of absorption of a generic formulation with that of a reference for mulation when given as equal labeled dose. The study will be randomized, open-label, single dose, two way crossover design with two-period, two-treatment and two-sequence under fed condition and at least 7 days washout period between the doses.

Title A Bioequivalence study of a randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence of Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg relative to Originator Sitagliptin and Metformin Hydrochloride Tablets 50 mg/500 mg in healthy Thai volunteers under fed condition. Objectives The primary objective is to compare the rate and extent of absorption of a generic formulation with that of a reference formulation when given as equal labeled dose. The secondary objective is to evaluate the safety after oral administration of both test and reference formulation in healthy Thai volunteers. Study Design Randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence under fed condition and at least 7 days washout period between the doses. Sample Size 34 Healthy Human Thai subjects. Two extra subjects if available, may be checked-in on the day of check in of period-I to compensate for any dropout prior to dosing of period-I. These subjects will be dosed if there are dropouts prior to dosing in period-I. If there are no dropouts, these subjects will be checked-out without being dosed after completion of dosing in period-I. Drug-Product Test-Product: Sitagliptin and Metformin tablets 50 mg/500 mg Reference-product: Sitagliptin and Metformin tablets 50 mg/500 mg Manufactured by: Patheon Puerto Rico, Puerto Rico 00674 Administration After an overnight fasting at clinical facility of at least 10 hours, each volunteer will receive high fat high calories breakfast which they are required to consume within 30 minutes and then a single dose of Sitagliptin and Metformin tablets 50 mg/500 mg of either test or reference with 250 mL of 20% glucose solution in water within 30 mins after starting the high fat high calories breakfast. Each volunteer will be allowed to drink water as desired except 1 hour before and after drug administration. The formulation is given in a crossover fashion as per the randomization schedule. After the administration, the subject's oral cavity will be checked by using flashlight to confirm complete medication and fluid consumption by pharmacist. Blood Schedule In each period, a total of 23 blood samples (approximately 5 mL each) will be collected pre-dose (0.00 hour) and at 0.333, 0.667, 1.000, 1.500, 2.000, 2.500, 3.000, 3.333, 3.667, 4.000, 4.333, 4.667, 5.000, 5.500, 6.000, 7.000, 8.000, 10.000, 12.000, 24.000, 36.000 and 48.0000hours after study drug administration, respectively. The sample collection at 24.00, 36.00 and 48.00 hours after dosing will be on ambulatory basis (i.e. on separate visit.). Sample Collection Blood samples will be collected through an indwelling catheter placed in a vein using disposable syringe or through fresh venipuncture with disposable syringes and needles. Approximately 5mL blood sample will be withdrawn and transferred to sample collection pre-labeled tubes containing K3EDTA as anticoagulant at each sampling time point. After collection of blood samples from each subject at each time point, samples will be centrifuged at 4000 rpm for 5 minutes at 4±2°C. After centrifugation, the plasma samples will be aliquoted into two pre-labeled cryovials for approximately 1 mL in original cryovial and leaving the remaining volume for the duplicate cryovial. Cryovials containing plasma sample will be stored at -70±10 °C. Analytical Method Sitagliptin and Metformin plasma concentration will be assayed as per international Guidelines/In-house SOP by using a validated LC-MS/MS method. Pharmacokinetic Parameters Primary pharmacokinetic parameter: Cmax, AUC0→t and AUC0→∞ Secondary pharmacokinetic parameter: Tmax, T1/2, Kel, AUC0→t/AUC0→∞ will be determined from the plasma concentration data of analytes. Statistical Analysis ANOVA, two one-sided tests for bioequivalence, for log-transformed pharmacokinetic parameters Cmax, AUC0→t and AUC0→∞ will be performed. Acceptance Criteria for Bioequivalence To be considered as bioequivalent, the 90% Confidence Interval of the geometric means ratio of Cmax, AUC0→t and AUC0→∞ of Sitagliptin and Metformin of test and reference products should be in the interval of 80.00-125.00% for the log-transformed data.

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