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Goal of the study is to estimate the pharmacokinetics (PK) of weekly 17OHPC in an obstetrical population and evaluate the effect of maternal body size on the PK parameters.
Prospective population PK study. Plasma samples and clinical variables were collected in pregnant women between 16 and 36 weeks gestational age (GA), carrying singleton pregnancy and receiving 17OHPC, 250 mg IM weekly for the prevention of recurrent spontaneous preterm birth. Liquid chromatography mass spectrometry was used to measure 17OHPC plasma concentrations. PK parameters and significant clinical covariates were estimated using mixed effect modeling. Population PK parameters were determined by nonlinear mixed effects modeling. Influence of demographic and clinical variables was evaluated by stepwise addition of covariates into the final population model. Four body size indicators were used in the model to predict PK parameters: Lean Body Weight (LBW), Total Body Weight (TBW), Body Mass Index (BMI) and Body Surface Area (BSA). The influence of maternal body size indicators on individual Bayesian PK estimates of 17OHPC were evaluated by ANOVA.
Fifty-four pregnant women, ages 18 to 44 years and BMIs 14.5 to 54.6 kg/m2, provided 114 17OHPC plasma samples concentration for analysis. A 1-compartment model with first order absorption satisfactorily described 17OHPC PKs. Compared to other body size indicators, lean body weight (LBW) best explained inter-subject variability, with coefficient of variation for apparent clearance (CL/F) decreasing 24.8% to 17.9% following addition of LBW into the population PK model. Age, race and GA did not influence 17OHPC PK. Mean (relative SE) population PK parameters were CL/F 151 (1.3%) L/h/50 kg LBW, apparent volume of distribution 59874 (1.8%) L and absorption rate constant 0.111 (41.5%) h-1. Mean + SD 17OHPC CL/F was significantly (p<0.001) higher in subjects with BMI > 35 kg/m2 (182+/-31 L/h/50 kg LBW) compared to subjects with BMIs <26 kg/m2 (133+/- 30 L/h/50 kg LBW), > 26 to 30 kg/m2 (137+/- 30 L/h/50 kg LBW), and >30 to 35 kg/m2 (144+/- 26 L/h/50 kg LBW).
Population PK analysis indicates 17OHPC apparent clearance significantly increases at BMI>35 kg/m2. Higher 17OHPC doses are required in subjects with BMI > 35 to achieve similar plasma concentrations compared to BMI < 35.