Suppression of ovulation and pharmacokinetics following subcutaneous administration of various doses of Depo-Provera®: a randomized trial

Abstract

Objectives: To identify the lowest dose of Depo-Provera that, when administered off-label subcutaneously, suppressed ovulation and had a pharmacokinetic profile consistent with a 4-month contraceptive effect. Study Design: We conducted a randomized, multicenter, parallel-group study to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of medroxyprogesterone acetate (MPA) after subcutaneous injection of three different doses of Depo-Provera. We randomized sixty women between 18 and 40 years of age at low risk of pregnancy with confirmed ovulation and body mass index of 18 to 35 kg/m 2 to receive a single injection of 45, 75 or 105 mg of Depo-Provera, or a single injection of Depo-subQ provera 104 as a reference drug (15 women per group) and followed them for 7.5 months. We evaluated suppression of ovulation as the primary outcome, and MPA concentrations, pharmacokinetic parameters, safety, and local tolerability as secondary outcomes. Results: Five women ovulated within four months of treatment initiation (three in the 45 mg group and two in the 75 mg group). MPA levels associated with ovulation were in general low, largely ≤ 0.2 ng/mL (the presumed contraceptive threshold). No women in either the 105 mg group or the Depo-subQ provera 104 group ovulated within four months. The PK parameters including C max , C 119 , and AUC 0−119 for these 2 groups were similar but not equivalent. Conclusion: A dose of 105 mg of Depo-Provera injected subcutaneously was the lowest tested dose that consistently suppressed ovulation and maintained serum MPA levels consistent with contraceptive effect for at least 4 months. The PK and PD results for the 105 mg dose were similar to Depo-subQ provera 104 over this period.

Ovulation suppression following subcutaneous administration of depot medroxyprogesterone acetate

“…Detailed characteristics of the 101 participants contributing to our analyses are in the previous manuscripts [ 10 , 11 ]. Briefly, the median age was 34 years (range 22–40); 35.6% self-identified as white and 64.4% identified as black or biracial; and the median body mass index (BMI; kg/m 2 ) was 26.6 (range 18.1–33.9; Table 1 ).…”

“…We performed a secondary analysis of 2 contemporary pharmacokinetics and pharmacodynamics studies of subcutaneously administered MPA conducted between September 2015 and May 2018 [ 10 , 11 ]. Briefly, FHI 360 Study number 702179 (Clinical Trial Registration Number NCT02456584) randomized 36 women from sites in the Dominican Republic and the USA to receive a single 150 mg (1 mL) or 300 mg (2 mL) subcutaneous injection of Depo-Provera, or two 104 mg (0.65 mL) subcutaneous injections of Depo-subQ at 3-month intervals, in a 2:1:1 ratio.…”

“…Participants who did not have an elevated progesterone concentration ≥4.7 ng/mL within 12 months of treatment initiation returned for weekly progesterone assessments in month 15 and (if still anovulatory) again in month 18 (the visit schedule within 12 weeks of injection and supportive pharmacodynamic measures are detailed elsewhere [10] ). FHI 360 Study number 834119 (NCT02732418) randomized 60 participants in the Dominican Republic, Chile, and Brazil to receive a single 45 mg (0.3 mL), 75 mg (0.5 mL), or 105 mg (0.7 mL) subcutaneous injection of Depo-Provera, or a single 104 mg subcutaneous injection of Depo-subQ, in a 1:1:1:1 ratio [11] . We measured serum progesterone levels at least weekly until ovulation was confirmed or month 7.5, whichever was earlier.…”

“…We measured serum progesterone levels at least weekly until ovulation was confirmed or month 7.5, whichever was earlier. However, all Study 834119 participants contributed a full 7.5 months of MPA testing, regardless of ovulation status (details of the testing algorithms, including other pharmacodynamic measures, are described elsewhere [11] ).…”

“…The side effect profile coupled with a lack of appreciable ovulation risk for Depo-subQ has led various researchers to consider regimens that could further reduce MPA exposure [9] . Here we present a secondary analysis of 2 contemporary pharmacokinetics and pharmacodynamics studies designed to inform such strategies [ 10 , 11 ]. Our initial aim was to characterize the distribution of serum MPA concentrations when ovulation returns.…”