Population pharmacokinetics of 17α-hydroxyprogesterone caproate in singleton gestation

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 (V_maternal/F). The final population mean estimates were: CL/F 1797 l/d, V_maternal/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.