Drospirenone (3 mg) + Ethinyl Estradiol (0.02 mg) Tablets Relative to Yaz®

Title A Bioequivalence study of a randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence of Drospirenone (3 mg) + Ethinyl Estradiol (0.02 mg) Tablets relative to Yaz® in healthy Thai female volunteers under fasting 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 female volunteers.

Study Design Randomized, open-label, single dose, two-way crossover design with two-period, two-treatment and two-sequence under fasting condition and at least 28 days washout period between the doses.

Sample Size 32 Healthy Human Thai female 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: Drospirenone (3 mg) + Ethinyl Estradiol (0.02 mg) Tablets Reference-product: Yaz® (Drospirenone (3 mg) + Ethinyl Estradiol (0.02 mg) Tablets) Manufactured by: Bayer Weimar GmbH und Co. KG, Germany

Administration After an overnight fasting at clinical facility of at least 10 hours, each volunteer will receive a single dose of two tablets of Drospirenone (3 mg) + Ethinyl Estradiol (0.02 mg) Tablets of either test or reference with 250 mL of drinking water. 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 10 mL each) will be collected pre-dose (0 hour) and at 0.333, 0.667, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.500, 4.000, 4.500, 6.000, 8.000, 12.000, 16.000, 24.000, 36.000, 48.000 and 72.000 hours after study drug administration, respectively. The sample collection at 36.000, 48.000 and 72.000 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 10 mL blood sample will be collected and transferred to 2 sample collection tubes containing K3EDTA as anticoagulant at each sampling time point. After collection of blood samples from all the subjects at each time point, samples will be centrifuged at 4000 rpm for 5 minutes at 4±2°C. After centrifugation, the plasma will be divided equally into another 3 cryovials for approximately 1.5 mL per each cryovial, Each cryovial will be set as Original (O), Duplicate (D) and Triplicate (T), respectively. Thereafter, Cryovials containing plasma sample will be stored at -70±10 °C.

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

Pharmacokinetic Parameters Drospirenone Primary pharmacokinetic parameter: Cmax, AUC0→ 72 and secondary pharmacokinetic parameter: Tmax, T1/2, Kel will be determined from the plasma concentration data of analytes.

Ethinyl Estradiol Primary pharmacokinetic parameter: Cmax, AUC0→t, AUC0→∞ and secondary pharmacokinetic parameter: Tmax, T1/2, Kel, AUC % Extrap will be determined from the plasma concentration data of analytes.

Statistical Analysis Drospirenone ANOVA, two one-sided tests for bioequivalence, for log-transformed pharmacokinetic parameters Cmax, AUC0→72 will be performed.

Ethinyl Estradiol ANOVA, two one-sided tests for bioequivalence, for log-transformed pharmacokinetic parameters Cmax, AUC0t, AUC0→∞ will be performed.

Acceptance Criteria for Bioequivalence Drospirenone To be considered as bioequivalent, the 90% CI of Cmax, AUC0→72 of Drospirenone of test and reference products should be in the interval of 80-125% for the log-transformed data Ethinyl Estradiol To be considered as bioequivalent, the 90% CI of Cmax, AUC0→t, AUC0→∞ of Ethinyl Estradiol of test and reference products should be in the interval of 80-125% for the log-transformed data.