Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation

Abstract

OBJECTIVE The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation. STUDY DESIGN Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks’ gestation (study 1) and 31 + 0 to 34 + 6 weeks’ gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery. RESULTS The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection. CONCLUSION The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.

Prevention of preterm delivery with 17-hydroxyprogesterone caproate: Pharmacologic considerations

“…Interestingly, CYP3A5 is the major CYP3A enzyme in more than half of African American adults compared to a third of Caucasians 23 . This finding could explain the increased clearance noted in African American pregnant women, but fails to explain the similar plasma concentrations for all races in the same study 24 . Not surprisingly, concomitant use of medications that are CYP3A inhibitors or inducers could lead to decrease or increase, respectively, in the clearance of 17-OHPC.…”

“…Across a dosing interval, maximal plasma concentration occurred a day after drug injection (Figure 2), but samples were not taken at earlier times. The area under the plasma concentration × time curve (AUC) of 17-OHPC was higher at 31–34+6 weeks compared to 20–24+6 weeks (21.0 vs. 24.3 ng/mL, p=0.007), suggesting sustained and continuous release of 17-OHPC from multiple administration sites 24 . In women with a singleton gestation, race did not alter drug concentrations; though the study was not powered to detect such an effect 24 .…”

“…In women with a singleton gestation receiving the recommended dose of 17-OHPC (250 mg weekly) there is a large variation in the maternal plasma concentrations of 17-OHPC (median 15.2 ng/mL, range 3.2–64.6 ng/mL) and the drug remains detectable weeks after the last injection 24 . The half -life of 17-OHPC is reported to be 16 days (±6 days 24 .…”

“…The half -life of 17-OHPC is reported to be 16 days (±6 days 24 . The prolonged half-life may result from a slow release of 17-OHPC from the castor oil depot and/or the maternal adipose tissue, which may also explain the detection of the drug in maternal samples 44 days after the last intramuscular injection.…”

Basic obstetric pharmacology

“…51 After intramuscular administration, its half-life ranges from 9 to 16 days in women with singleton gestation. 8 Body mass index (BMI) has been found to contribute to the inter-individual differences in trough plasma concentrations and area under the curve of 17-alpha hydroxyprogesterone caproate, with women of higher BMI having a lower drug exposure as determined by AUC. 7 Increased progesterone levels or co-administrated medications that are inducers or inhibitors of CYP3A (Table 4) during pregnancy may also account for some of the large variation in plasma 17-alpha hydroxyprogesterone caproate concentrations that is seen in pregnant patients.…”