A Comparative Pharmacokinetic Study of ORTHO EVRA (a Transdermal Contraceptive Patch) and CILEST (an Oral Contraceptive) in Healthy Female Volunteers

ORTHO EVRA® is a combination, monophasic transdermal contraceptive patch containing 6 mg of norelgestromin (NGMN) and 0.75 mg of ethinyl estradiol (EE), and delivering to the systemic circulation an average of 150 µg/day of NGMN and 20 µg/day of EE. CILEST® is an oral contraceptive tablet containing 250 µg of norgestimate (NGM) and 35 µg of ethinyl estradiol (EE). Although the multiple-dose pharmacokinetics of the active serum progestin and estrogen analytes following administration of the ORTHO EVRA® formulation and OrthoCyclen (same as CILEST®) has been evaluated previously in separate studies, the multiple dose pharmacokinetics has not been evaluated in a comparative manner in a single study. The present study is designed to directly compare the total exposure and pharmacokinetics, over comparable time intervals (Week 1 of Cycle 1 and Week 3 of Cycle 2), of NGMN, NG, and EE from ORTHO EVRA® and CILEST® in a single study, designed as a randomized, crossover study. Since EVRA® is worn for 7 days and CILEST® is a once-daily tablet, pharmacokinetics will be estimated over different time periods ORTHO EVRA® (7 days) and CILEST® (Days 1 and/or 7 of a 7 day period) during each cycle. Pharmacodynamic parameters of estrogenicity are determined and compared to assist in the interpretation of the pharmacokinetic data.

This is a single center, randomized, open-label, two-way crossover, pharmacokinetic study of ORTHO EVRA® and CILEST®. The subject population is to be comprised of 32 healthy female volunteers between the ages of 18 and 48 years and having a body mass index (BMI) between 18.0 and 29.9 kg per meter squared. The study consists of a pretreatment phase (a screening period up to 21 days), an open-label treatment phase (two 28-day cycles of 1 treatment, a washout period of 28 days, and cross-over to two 28-day cycles of the other treatment), and a post-treatment phase (a follow-up or early withdrawal visit). Treatment Day 1 is the first day of menses, or within 5 days after the first day of menses. In one treatment period, subjects wear an ORTHO EVRA® patch on their abdomen or buttock (based on the randomization schedule) applied once weekly for 3 consecutive weeks during each of two 28-day cycles. ORTHO EVRA® will be applied and removed by the investigator (or designated study personnel), on Days 1 (application only), 8, 15, and 22 (removal only) of each cycle. In the other treatment period, subjects take CILEST® tablets once daily for the first 21 days of each cycle for two 28-day cycles. CILEST tablets will be administered to the subject with 225 mL (7.5 oz) of water by the investigator or designated personnel on Days 1 through 8 of Cycle 1 and Days 18 through 21 of Cycle 2. On days when the subject is not required to be at the study unit, the subject will self-dose at home (on Days 9 through 21 of Cycle 1 and Days 1 through 17 of Cycle 2). Neither the ORTHO EVRA® patch nor CILEST® tablets are used on Days 22 to 28 (the 4th week) of any cycle, during which subjects may experience withdrawal bleeding. The total duration of the open-label treatment phase is approximately 5 months.

The primary outcome of the study is a comparison of the total exposure and pharmacokinetics, based on comparable intervals, of NGMN, NG, and EE. Blood samples will be drawn during Week 1 of Cycle 1 and Week 3 of Cycle 2 for analysis of plasma NGMN (total and anti and syn isomers), NG, and EE concentrations. Pharmacokinetic parameters, such as Cmax, tmax, and AUC will be estimated by non-compartmental methods. Safety is assessed by monitoring for the incidence and severity of adverse event reports, clinical laboratory tests, vital signs, physical and gynecological examination and an electrocardiogram (ECG). The expectation is that the ratios of exposure between these products and of the ratios of NG/NGMN between these products will be similar. However, the confidence intervals around these ratios are not required to fall within 80-125%. Treatment 1: ORTHO EVRA® transdermal patch, applied once weekly for 3 consecutive weeks of each cycle for two 28-day cycles. Treatment 2: CILEST® tablets, taken once daily by mouth for 21 consecutive days of each cycle, for two 28-day cycles. There is a 28-day washout between treatments.