Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin) compared with vaginal gel in healthy reproductive-aged female subjects

Objective: To determine pharmacokinetic profiles of two times a day and three times a day dosage regimens of Endometrin, a micronized progesterone vaginal insert for luteal support in assisted reproductive technology, compared with a gel. Design: A single-center, randomized, open-label, single-day, and multiple-day (5 days) parallel design pharmacokinetic study. Setting: University clinical research unit. Patient(s): Three groups of six healthy subjects, ages 18 to 40 years. Intervention(s): Endometrin vaginal inserts two times a day or three times a day, or gel daily. Main Outcome Measure(s): Pharmacokinetic profiles. Result(s): Progesterone serum concentrations increased rapidly following administration of Endometrin vaginal insert, producing higher peak concentrations (C_max) and clearing faster than gel. On the single day of dosing, mean C_max was 17.0 ± 2.7 ng/mL in the two times a day group, 19.8 ± 2.9 ng/mL in the three times a day group, and 6.82 ± 1.69 ng/mL in the gel group. Endometrin treatments reached steady state within the first 2 days (24-36 hours), much more rapidly than the gel, which had not reached steady state by 5 days. At 5 days, the Endometrin treatments produced sustained progesterone concentrations exceeding 10 mg/mL across 24 hours. Conclusions: Endometrin vaginal inserts reached higher C_max, produced greater systemic exposure (area under the curve 0-24), achieved steady state more rapidly, and cleared more rapidly after termination of therapy than the comparator.