Esomeprazole Magnesium Dihydrate 40 mg Tablets Relative to Nexium 40 mg Tablets Under Fed Condition

Title A Bioequivalence study of a randomized, open-label, single dose, full replicate crossover design with four-period, two-treatment, and two-sequence of Esomeprazole magnesium dihydrate 40 mg tablets relative to Nexium 40 mg tablets 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, full replicate crossover design with four-period, two-treatment, and two-sequence under fed condition and at least 7 days washout period between the doses.

Sample Size 40 Healthy Human Thai subjects. Four 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: Esomeprazole 40 mg gastro-resistant tablets Reference-product: Nexium® 40 mg tablets Manufactured by: AstraZeneca AB, Kingdom of Sweden

Administration After an overnight fasting at clinical facility of at least 10 hours prior to high fat high calorie breakfast, each volunteer will receive a single dose of Esomeprazole 40 mg gastro-resistant tablets of either test or reference with 250 mL of drinking water after starting high fat high calorie breakfast. Each volunteer will be allowed to drink water as desire 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 21 blood samples (approximately 5 mL each) will be collected pre-dose (0.00 hour) and at 0.50, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 5.50, 6.00, 6.50, 7.00, 8.00, 9.00, 10.00, 12.00, 16.00 and 24.00 hours after study drug administration, respectively.

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 5 mL blood sample will be withdrawn and transferred to sample collection pre-labeled tubes containing K3EDTA as anticoagulant at each sampling time point. Invert collection tube 3-5 times immediately after collection. After collection, all samples transfer into centrifugation room at controlled temperature (2-8 °C). 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. The plasma will be added in the pre-added buffer of 0.5M Sodium hydrogen carbonate in Milli-Q water to the pre-labeled cryovials, proper adjustments for buffer addition which will be permissible but the final composition of buffer in plasma will be 5% of total volume. The cryovials will be then vortexed for 30 seconds on multitube vortexer. Cryovials containing plasma sample will be stored at -70±10 °C.

Analytical Method Esomeprazole plasma concentration will be assayed as per international Guidelines/In-house SOP by using a UPLC-MS/MS method.

Pharmacokinetic Parameters Primary pharmacokinetic parameter: Cmax, AUC0→t and AUC0→∞ and 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,

1. The 90% CI of AUC0→t and AUC0→∞ of Esomeprazole of test and reference products of the log-transformed data should be between 80.00-125.00%.
2. The 90% CI of Cmax of Esomeprazole of test and reference products of the log-transformed data should be in the acceptance criteria based on the within-subject variability seen in the study using scaled-average-bioequivalence as recommended in the 2010 EMA guideline