Quantitative Prediction of the Role of Placental Efflux to Optimize Dosing Regimens of Dexamethasone and Betamethasone to Prevent Respiratory Distress Syndrome

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IntroductionRespiratory distress syndrome is one of the major causes of newborn deaths. Dexamethasone (DEX) and Betamethasone (BET) may promote fetal lung maturation when administered to pregnant women at risk of preterm birth. Usually, DEX‐phosphate (6 mg) is administered IM q 12 hrs over 48 hrs while BET is administered IM as a 50:50 phosphate and acetate combination (12 mg total) q 24 hrs over 48 hrs. Recent non‐clinical trials suggest lower concentration would result in effective treatment for these drugs. In sheep, fetal BET plasma concentrations >1 ng/mL appears to adequately promote fetal lung maturation. Therefore, there is a need to optimize the dosing regimen of these drugs. DEX and BET are substrates of P‐gp, a placental efflux transporter, that can reduce their fetal plasma concentrations. We have recently developed a maternal‐fetal PBPK model to predict maternal‐fetal plasma concentrations of drugs throughout pregnancy. The model has been populated with physiological changes observed in pregnancy including that in hepatic activity of CYP enzymes. Using this model, our aims were to 1) predict maternal plasma concentration‐time profiles of DEX and BET, after IM administration, and compare them with those observed; 2) determine the extent of placental P‐gp activity necessary to match the predicted and observed fetal DEX/BET plasma concentrations; 3) use these data to design maternal dosing regimens of DEX and BET that minimize maternal plasma concentrations while maintaining fetal plasma concentrations > 1 ng/ml.MethodNon‐pregnant PBPK model for both drugs was developed in SimCYP where hepatic intrinsic clearance by CYP3A (CLhep,int), renal clearance and absorption rate constants of IM DEX and BET, were optimized based on literature data. A single first‐order absorption rate was used for IM DEX‐phosphate. Distinct absorption rate constants were used for IM BET‐phosphate and IM BET‐acetate. The maternal PBPK model was developed in MATLAB Simulink and populated with maternal gestational age‐dependent changes as well as placental passive diffusion and fetal hepatic clearance of the drugs. Theoretical DEX and BET fetal plasma concentration‐time profiles were simulated with varying magnitudes of P‐gp efflux until their predicted fetal plasma concentration‐time profiles adequately encompassed the observed data and the fetal PK parameters (AUC and Cmax) fell within 0.8 to 1.25‐fold of observed values.Results and DiscussionBoth non‐pregnant and pregnancy PBPK models for DEX were verified with the observed data. The pregnancy model for BET (i.e CLhep, int) needed to be optimized to describe the observed maternal plasma concentration data. Sensitivity analysis showed that the fraction of DEX and BET transported by placental P‐gp needed to be 0.6 and 0.5, respectively, to best describe the observed fetal plasma concentration data. Using these data, we are devising dosing regimens of DEX and BET for pregnant women that have the potential to maximize their efficacy and minimize their toxicity. These dosing regimens will be presented.Support or Funding InformationThis work is Supported by Bill & Melinda Gates Foundation grant OPP1190468