Multigeneration reproductive study of hydroxyprogesterone caproate (HPC) in the rat: laboratory results and clinical significance.

To demonstrate reproductive safety of a new commercial product for reducing the risk of preterm birth, HPC (17α-hydroxyprogesterone caproate, Makena; manufactured by Baxter Pharmaceutical Solutions, Bloomington IN for Ther-Rx Corporation, St. Louis, MO) was administered intramuscularly in Charles River LaboratoryCD strain rats. HPC was given at intervals equal to the half-life measured in rats during three phases of embryo-fetal development: during the period of ovarian development (RP1, days 8, 14, and 20), following implantation of the embryo (TP, days 6, 12, and 18), and, corresponding to the start of the drug in week 16 or later in humans, after gonadal formation including differentiation of the testes (RP2, day 17). Dose levels up to 30× the human therapeutic doses were utilized including 0 (vehicle), 5, 25, and 150 mg/kg (volume 0.6 ml/kg). Four groups of 25 time-mated rats each were used for each phase. In addition, equal numbers of naïve (untreated) rats of opposite gender were used for F(1) breeding studies. HPC did not produce any consistent test-article-related findings in the treated F(0) dams, their developing F(1) fetuses and did not affect the ability of the latter to produce a viable F(2) generation. The F(1) offspring did not evidence any adverse effects during their behavioral, sensory, and developmental assessments, including teratogenicity. Based on the cumulative data obtained from rats treated over two generations and during development in this study, the No-observable-effect-level (NOEL) was established as 150 mg/kg. This study supports the absence of reproductive toxicity with HPC in published studies in animal models and in human clinical trials.