Original research articlePharmacokinetics, ovulation suppression and return to ovulation following a lower dose subcutaneous formulation of Depo-Provera®
Introduction
Depo-Provera® (medroxyprogesterone acetate, intramuscular injection [IM DMPA]); is a highly effective injectable contraceptive that has been used in the United States for over 10 years [1], and worldwide for over 30 years [2]. Over the past decade, this option has become an increasingly popular choice for hormonal contraception among US women, and the decline in unintended pregnancy rates during this time has been attributed in part to the increased use of long-acting contraceptives such as IM DMPA [3], [4]. Requiring only one injection every 3 months, this method results in a low “typical use” failure rate that is comparable to the rate with “perfect use” (0.3%) [5]. Thus, typical use rates for IM DMPA are similar to those reported for the 5-year Mirena® (levonorgestrel intrauterine system) and surgical sterilization, and much better than the typical use rate for the most prevalently used hormonal method, daily oral contraceptives (OCs) [6], [7], [8], [9]. This consistency between perfect use and typical use may be attributable to both the need for less frequent dosing and the fact that antiovulatory concentrations of medroxyprogesterone acetate (MPA) are achieved within 24 h of injection, providing immediate protection against pregnancy when used within the first week of menses [10]. Among currently available hormonal methods, IM DMPA and Mirena are immediately effective, whereas oral, patch and vaginal ring contraceptives generally require a backup method for the first 7 days of use [11], [12].
The new, lower dose formulation of Depo-Provera (104 mg/0.65 mL) allows administration by subcutaneous (SC DMPA) rather than intramuscular injection, and is expected to be therapeutically equivalent to the original formulation. This formulation is expected to have comparable if not improved tolerability relative to the intramuscular formulation, due to its lower dose. Although similar trends have been seen with lowering of hormone dose in combination OCs (i.e., estrogen), concerns include the possibility of reduced efficacy in general or in certain patient subtypes, such as those with higher body mass index (BMI) [13]. Another concern that may be raised for methods that have a longer duration of contraceptive effect is ease of reversibility and potential for delayed return to fertility.
The objectives of this pharmacokinetic/pharmacodynamic (PK/PD) study were to assess and compare the efficacy and duration of ovulation suppression, and return to ovulation at 12 months following a single injection of either SC DMPA or IM DMPA. Additional objectives were to determine the PK profile of MPA when given via subcutaneous route and to assess the potential influence of BMI and ethnicity. For the purpose of comparison, data on 24 women given SC DMPA from a separate PK study conducted in Singapore are included and will be addressed in the discussion (data on file).
Section snippets
Methods
The dose selection for SC DMPA was determined in a previous dose-ranging PK/PD study, in which a total of 47 women received a single injection of 50 mg, 75 mg, 100 mg or 150 mg/0.5 mL SC DMPA (data on file). The 100-mg injection was the lowest dose that effectively suppressed ovulation for at least 91 days. The SC DMPA developed for the current trial is a new formulation with 16% weight/volume resulting in a final dose of 104 mg/0.65 mL. Therefore, the formulation and composition of SC DMPA
Demographic characteristics
A total of 19 and 39 patients were considered evaluable in the IM DMPA and the SC DMPA groups, respectively. Table 1 presents the demographic characteristics of evaluable subjects from this study (conducted at a single center in Los Angeles, CA). For the purpose of comparison, data are also presented for 24 Asian women who received SC DMPA in a separate study conducted in Singapore. The Singapore study data will be addressed in the discussion portion of this article. Women in the IM DMPA and SC
Discussion
This PK/PD study demonstrated that a single injection of SC DMPA (a new formulation containing 104 mg MPA/0.65 mL) provided immediate suppression of ovulation and consistently suppressed ovulation in study subjects over the 91-day (13-week) dosing interval. Analysis of the PK of MPA after SC injection showed similar MPA parameters for black, white, and Asian subjects, indicating that the efficacy of the lower-dose formulation was independent of race. Furthermore, suppression of ovulation was
Acknowledgements
The authors would like to thank Dr. Yeong Cheng Toh, MD, of the KK Women's and Children's Hospital in Singapore, China, for supplying pharmacokinetic data in Asian women from a separate study conducted in Singapore.
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