Lunelle™ monthly contraceptive injection (medroxyprogesterone acetate and estradiol cypionate injectable suspension): steady-state pharmacokinetics of MPA and E 2 in surgically sterile women

Abstract

The steady-state pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate (MPA) and estradiol (E 2, released from E 2C by esterase enzymes) were characterized after administration to surgically sterile women. This report describes the pharmacokinetics of this multiple-dose and open-labeled study (pharmacodynamics are reported in a subsequent article in this issue). Women with regular menstrual cycles were studied for one control cycle, 3 consecutive treatment months, and 3–5 months of follow-up. Blood samples were drawn before each monthly dose and at specified time points after the third monthly injection. A total of 16 women were enrolled, 14 of whom completed the study. These 14 women (13 white, one black) ranged in age from 28 to 43.4 years, in body weight from 47.6 to 68.9 kg, and in height from 150 to 175 cm. Mean serum MPA concentrations peaked in the first week after administration of MPA/E 2C (Lunelle™ Monthly Contraceptive Injection). The mean MPA C max and AUC 0−t(last) were 1.25 ng/mL and 32.13 ng · day/mL, respectively. Serum MPA concentrations declined with a mean terminal half-life of 14.7 days, indicating that absorption from the injection site is prolonged after administration of MPA/E 2C. The time for MPA concentrations to fall below the lower limit of quantitation (i.e., <10 pg/mL) after the third injection ranged from 63 to 84 days. The average MPA trough (C min, day 28) concentrations for the three consecutive monthly injections ranged from 0.44 to 0.47 pg/mL, indicating that steady-state conditions were achieved after the first injection. The MPA C min values were well above threshold levels required to suppress ovulation throughout the injection interval. Absorption of E 2 from the injection site was also prolonged after injection of MPA/E 2C. Mean concentrations of E 2 peaked at approximately 2 days after the third injection, and the average C max was 247 pg/mL. Serum E 2 levels declined with a terminal half-life of approximately 8 days; E 2 levels returned to baseline (typically, approximately 100 pg/mL) by 14 days after each injection. The average trough (C min, day 28) levels for E 2 ranged from 40 to 55 pg/mL. The results of this study demonstrate that steady-state conditions are achieved after the first injection of MPA/E 2C; no further MPA or E 2 accumulation occurs beyond the first injection. Furthermore, the E 2 peak observed after injection of MPA/E 2C is similar to the nontreated preovulatory E 2 range and returns to baseline levels by approximately 14 days after injection.