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Aims: 17α-hydroxyprogesterone caproate (17-OHPC) reduces the rate of preterm birth in women with a prior preterm birth. Limited data exist on the pharmacokinetics (PK) of 17-OHPC or the plasma concentrations achieved during therapy. In this study, we evaluated the population PK of 17-OHPC in pregnant subjects with singleton gestation and also evaluated intrinsic and extrinsic factors that may potentially affect 17-OHPC PK in this patient population., Methods: Sixty-one women with singleton pregnancies participated in this trial. Subjects received weekly intramuscular injections of 250 mg 17-OHPC in 1 ml castor oil from the time of enrolment (16 0/7 weeks - 20 6/7 weeks) up to 35 weeks gestation or until delivery. Blood samples were obtained between 24 and 28 weeks, between 32 and 35 weeks and over a 28-day period beyond the last injection. Maternal and/or cord blood were obtained at delivery. Data analysis was performed by nonlinear mixed effects modelling (NONMEM(®) )., Results: The 17-OHPC PK were best described by a model with one maternal compartment and one fetal compartment, with first-order absorption and elimination from the maternal compartment. Maternal body weight was a significant covariate for both clearance (CL/F) and volume of distribution (Vmaternal /F). The final population mean estimates were: CL/F 1797 l/d, Vmaternal /F 32 610 l and mother to cord rate constant 0.005 day(-1) . This report describes for the first time the population PK of 17-OHPC in singleton pregnancy., Conclusions: The population PK study reported here represents the initial steps in understanding and optimizing 17-OHPC therapy for preventing preterm birth., (© 2016 The British Pharmacological Society.)

Little information is available in the literature regarding the expression and activity of transporters in fetal human liver or cultured cells. A synthetic progesterone structural analog, 17α-hydroxyprogesterone caproate (17-OHPC), is used in the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion). 17-OHPC has been reported to traverse the placental barrier and gain access to fetal circulation. In this study, the role of transporters in the disposition of 17-OHPC in fetal and adult human hepatocytes was examined. Progesterone metabolites have been reported to induce trans-inhibition of bile acid transporter, ABCB11. Thus, we investigated the effect of 17-OHPC or its metabolites on [(3)H]taurocholic acid transport in sandwich-cultured human fetal and adult hepatocytes. 17-OHPC was taken up rapidly into the cells and transported out partially by an active efflux process that was significantly inhibited by cold temperature, cyclosporine, verapamil, and rifampin. The active efflux mechanism was observed in both adult and fetal hepatocyte cultures. 17-OHPC produced a concentration-dependent inhibition of taurocholate efflux into canaliculi in sandwich-cultured adult and fetal human hepatocytes. However, given the high concentrations required to cause inhibition of these transport processes, no adverse effects would be anticipated from therapeutic levels of 17-OHPC. We also evaluated the expression of various hepatic transporters (ABCB1, ABCB4, SLCO1B1, SLCO1B3, SLCO2B1, ABCB11, SLC10A1, ABCC2, ABCC3, ABCC4, and ABCG2) in fetal and adult hepatocytes. With the exception of ABCB4, all transporters examined were expressed, albeit at lower mRNA levels in fetal hepatocytes compared with adults.

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., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Objective: The purpose of this study was to define the pharmacokinetic parameters of 17-hydroxyprogesterone caproate (17-OHPC) in multifetal gestation., Study Design: Blood was obtained at 24-28 weeks' gestation and at 32-35 weeks gestation in 97 women with twin and 26 women with triplet gestation who were receiving 17-OHPC. Six of the women with twins had daily blood sampling for 7 days between 24 and 28 weeks' gestation, and pharmacokinetic parameters were estimated with the use of noncompartmental analysis. Modeling was applied to estimate the population parameters and to simulate various treatment scenarios., Results: The apparent half-life of 17-OHPC was 10 days. Body mass index significantly impacted 17-OHPC concentrations, but fetal number and parity did not. Apparent clearance was significantly greater in African American than in white women (P = .025)., Conclusion: This is the first pharmacokinetic analysis of 17-OHPC in pregnant women. Determination of half-life, covariates that affect plasma 17-OHPC concentrations, and the modeling of drug behavior provide insights into this drug's pharmacologic properties during multifetal pregnancy., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Preterm delivery (i.e., delivery before 37 completed weeks of gestation) is a major determinant of neonatal morbidity and mortality. Until recently, no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17alpha-hydroxyprogesterone caproate (17-OHPC) was shown to reduce the rate of preterm birth by 33% in a group of high-risk women. Limited pharmacologic data exist for this drug. Previous studies have shown that CYP3A is involved in the metabolism of 17-OHPC. In this study, we evaluated the metabolism of 17-OHPC in adult and fetal human hepatocytes and in expressed cytochrome P450 enzymes. 17-OHPC was metabolized by expressed CYP3A7 and by fetal hepatocytes. The metabolite profile was qualitatively different between expressed CYP3A4 and CYP3A7. Expressed CYP3A4 demonstrated a significantly higher (>10 times) capacity to metabolize 17-OHPC than CYP3A7. Based on retention times, two unique metabolites were observed in the fetal and adult hepatocyte systems along with one common metabolite. The intrinsic clearance of 17-OHPC by fetal hepatocytes was observed to be one-half of that in adults. In summary, this study demonstrates that fetal hepatocytes and, in particular, the fetal form of CYP3A (i.e., CYP3A7) can metabolize 17-OHPC.

A sensitive and specific assay method for the simultaneous quantitation of 17alpha-hydroxyprogesterone caproate (17-OHPC), 17alpha-hydroxyprogesterone (17-OHP), and progesterone (P) in human plasma using high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) was developed and validated. Plasma samples were processed by a solid phase extraction (SPE) procedure using Oasis((R)) HLB extraction cartridge prior to chromatography. Medroxyprogestrone acetate (MPA) was used as the internal standard. The compounds were separated using Waters C18 Symmetry analytical column (3.5 microm, 2.1 mm x 50 mm) using a gradient elusion with a mobile phase consisting of 5% methanol in water [A] and methanol [B], with ammonium acetate (2mM) and formic acid (0.1%) being added to both [A] and [B], at a flow rate 0.3 ml/min. The retention times for 17-OHPC, 17-OHP, P and MPA were 4.5, 1.5, 2.5 and 2.2 min, respectively, with a total run time of 7 min. The analytes were detected by a Micromass Quattro Micro triple quadrupole mass spectrometer in positive electron spray ionization (ESI) mode using multiple reaction monitoring (MRM). The extracted ions monitored following MRM transitions were m/z 429.10-->313.10 for 17-OHPC, m/z 331.17-->97.00 for 17-OHP, m/z 315.15-->109.00 for P and m/z 387.15-->327.25 for MPA (IS). The assay was linear over the range 1-200 ng/ml for 17-OHPC and 17-OHP, and 2-400 ng/ml for P, when 0.4 ml of plasma was used in the extraction. The overall intra- and inter-day assay variation was <15%. No significant variation in the concentration of 17-OHPC, 17-OHP or P was observed with different sample processing and/or storage conditions. This method is simple, allows easy, accurate and reproducible measurement of 17-OHPC, 17-OHP and P simultaneously in human plasma, and is used to evaluate the pharmacokinetics of 17-OHPC in pregnant subjects.