Preeclampsia increases maternal exposure to betamethasone in pregnancy: a population pharmacokinetic study
Sam Schoenmakers1*, Letao Li2*, Irwin Reiss, Karel Allegaert2,8,9,10, Sjoerd van den Berg4, Bertrand van Zelst4, Ron van Schaik5, Philip DeKoninck1, Emma Ronde1, S.D.T. (Sebastiaan) Sassen2, Sinno HP Simons3+ , Birgit CP Koch2,6,7+.
1. Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, The Netherlands 2. Department of Hospital Pharmacy, Erasmus University Medical Center, The Netherlands 3. Department of Pediatrics, Division of Neonatology, Erasmus University Medical Center, Rotterdam, The Netherlands 4. Department of Internal Medicine, Division of Endocrinology, Erasmus University Medical Center, the Netherlands 5. Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands 6. Center for Antimicrobial Treatment Optimization Rotterdam (CATOR), the Netherlands 7. Rotterdam Clinical Pharmacometrics Group, the Netherlands 8. Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven Belgium 9. Department of Development and Regeneration, KU Leuven, Leuven Belgium 10. Leuven Child and Youth Institute, KU Leuven, Leuven Belgium
Objectives: Maternal dosing of antenatal corticosteroids (ACS) to improve fetal lung development in case of imminent preterm birth has remained the same “one dose fits all” for years, although dosing is not optimal based on side effects and variable efficacy. The first step to improve ACS dosing is to understand factors that may influence maternal exposure. To improve maternal dosing of corticosteroids, aiming for similar exposure in all women, by establishing a population pharmacokinetic model of betamethasone in pregnant women including analyses of clinically relevant covariates and cytochrome P450 3A4 polymorphism.
Methods: A prospective, single center study was performed in pregnant women admitted at the Department of Obstetrics at the Erasmus University Medical Center with a high risk for preterm birth (with a gestational age between 23+5 and 33+6 weeks). Women received betamethasone (2 intramuscular doses of 12 mg with a 24 hours intervals) as part of standard of care according to local protocol. Betamethasone serum concentrations were determined in serial venous blood samples. Population pharmacokinetic modelling was performed using Non-linear mixed effects models (NONMEM). The data were first fitted to a one-compartment model and subsequently more complex models and inter-individual variability (IIV) on CL, V and Ka. A combined proportional and additive residual error model was used to describe the residual error in the model predicted serum concentrations. Maternal and pregnancy variables like total body weight (TBW), lean body weight (LBW), body surface area (BSA), BMI at admission, preeeclampsia, gestational age, maternal age, singleton or multiple gestation and CYP3A4*22 genotype were included in covariate analysis. Goodness of fit plot, bootstrap and visual-predictive-check (VPC) were applied to test the robustness of the parameter estimations. To show an illustration of the covariate effect on the exposure of betamethasone, deterministic simulations were performed by using NONMEM.
Results: The pharmacokinetic dataset of betamethasone levels used for PK population modeling was based on a total of 28 pregnant women who contributed 194 serum samples for analysis. The model was best described using a two-compartment model. The population mean estimate for absorption constants (Ka), central volume of distribution, peripheral distribution volume, clearance and half-life for an average patient were 1.7 h-1 (IIV 27%), 46.1L, 109L, 14.4 L/h (IIV 5%) and 7.4h, respectively. Pre-eclampsia were identified as the only important covariates on the betamethasone clearance. Betamethasone clearance in preeclamptic women was 60% lower compared to non-preeclampsia women (9.35 versus 15.78 L/h) resulting in a 40% median increase in betamethasone exposure (1567 versus 1114 ng.h/ml).
Conclusions: Our population PK model showed that maternal betamethasone exposure in women with preeclampsia is significantly increased. Pending assessment of fetal exposure, our data suggest that a significant dose reduction of betamethasone may be needed to reach similar maternal exposure in preeclampsia.