A novel progesterone releasing intravaginal ring for luteal phase support: pharmacokinetics and safety in a sheep model

Abstract

To evaluate the in vitro release and in vivo pharmacokinetics and local tolerability of a novel, segmented ethylene-vinyl acetate (EVA) intravaginal ring (IVR) (DARE-FRT1) delivering progesterone (P) in drug-naive female Dorset crossbred sheep. These rings are being developed to provide luteal phase support and supplementation during ART cycles and early pregnancy. IVRs capable of releasing P at 4 mg/d, 8 mg/d and 12 mg/day were administered to female sheep to assess the pharmacokinetics and safety compared to vaginal administration of Crinone 8% gel or Prometrium (200 mg) capsules. IVRs were prepared by hot-melt extrusion to create segments of varying length and drug content. The appropriate segments were used to create segmented IVRs capable of releasing P at rates of approximately 4, 8, and 12 mg/day. Release rates of P from the three IVR formulations were measured in vitro to determine whether the target release rates had been attained. Release rates were tested using 200 mL 0.5% sodium dodecyl sulfate as a release medium, in shakers at 37°C. Sampling (2 mL) was conducted on Days 1-4, 7-11, and 14. Animals were randomized into one of six treatment groups: Group 1) Crinone® 8% gel (90 mg); group 2) Prometrium® 200 mg capsules; group 3) placebo IVR; group 4) P IVR 4 mg/day; group 5) P IVR 8 mg/d, or group 6) P IVR 12 mg/d. All IVRs were inserted on Day 1 remained in place through Day 14; the rings were removed and a new ring inserted on Day 15. The second ring remained in place until Day 29. Blood samples were taken at scheduled times for pharmacokinetic (PK) analysis. Concentrations of P in plasma were measured using a validated LC/MS/MS method. Postmortem examinations performed on all IVR groups included vaginal irritation, macroscopic and microscopic evaluations, including irritation scoring and histopathology. Following a relatively large amount of released P on Day 1, in vitro release rates confirmed that P was released at approximately 4, 8, or 12 mg/d over Days 2 - 14. IVRs were retained over 28 days in all animals with two exceptions. Clinical observations showed no significant abnormal findings in any group. PK analysis in animals showed sustained release of P from Days 0 through 14 of ring use. PK parameters from the three different IVRs were consistent with the in vitro release rates. Cavg increased in a dose-related manner, with mean values of 455, 682, and 1,040 pg/mL for the 4, 8 and 12 mg/day IVR groups, respectively. The lower dose Crinone gel (90 mg P) showed substantially greater relative bioavailability compared with the higher dose Prometrium capsules (200 mg P). Irritation scores and microscopic assessments were consistent with the IVRs being well tolerated following 28 days of exposure. The data obtained from this study demonstrate that the segmented DARE-FRT1 EVA-based IVRs are capable of sustained release of P at different rates over a 14-day period. The rings were well tolerated with minimal to mild local irritation. These results suggest the rings are suitable for evaluation in a Phase 1 clinical study in women for PK and safety.