Evaluation of the single dose and steady state pharmacokinetics of a progeseterone vaginal ring

Abstract

OBJECTIVE: To evaluate systemic progesterone pharmacokinetics following intravaginal administration during two 7-day application cycles of a weekly progesterone vaginal ring (VR) in postmenopausal women pre-treated with estrogen. DESIGN: Open-label, one-treatment, two dose bioavailability study. MATERIALS AND METHODS: A total of 30 postmenopausal women (mean age 55.6) were pretreated with 28 days of oral estradiol prior to VR insertion and plasma pharmacokinetics of the weekly ring were evaluated during 2 consecutive 7-day dosing cycles. The second ring was removed 168 hours (Day 15) after insertion (336 hours after the first ring insertion). Blood sampling occurred from 48 hours prior to the first ring insertion (Day-2) until 48 hours after the second ring removal (384 hours after the first ring insertion or Day 17, two days after removal of the second ring). The following pharmacokinetic parameters were calculated: 1st ring insertion: Cmax, Tmax, AUC 0-168 and Cavg,ss, 2nd ring insertion: Cmax, Tmax, AUC 168-336, AUC 168-384, AUC 168-inf, Cavg,ss, Kel, and T1/2. Prior to performing any analysis, all post-dose samples were baseline-corrected. RESULTS: Steady state plasma concentrations exceeding 8 ng/mL were attained 96 hours after the first ring insertion. Except for a brief and modest fluctuation in the few hours following insertion of the second ring, plasma concentrations for the entire 7-day wear period of the second ring were essentially constant. No accumulation was observed with the use of the second ring. The AUC for the first 24-hour period was nearly identical to the AUCs for the other 6 24-hour periods in the 7-day wear period, implying a zero-order release rate. Removal of the ring resulted in a rapid drop in plasma concentration. CONCLUSION: The weekly progesterone VR provides consistent plasma levels of progesterone with minimal fluctuation between doses, rapid onset of steady state, and rapid decline after discontinuation.