Prediction of Maternal and Fetoplacental Concentrations of Cefazolin, Cefuroxime, and Amoxicillin during Pregnancy Using Bottom-Up Physiologically Based Pharmacokinetic Models

Abstract

Concerns over maternal and fetal drug exposures highlights the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modelling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiological changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared to the observed data.Fully bottom-up feto-placental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in non-pregnant and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed PK data reported in 9 maternal (5 fetoplacental) studies for cefuroxime, 10 maternal (5 fetoplacental) studies for cefazolin, and 6 maternal (2 fetoplacental) studies for amoxicillin.Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively use for maternal/fetal risk assessment following maternally administered drugs or unintended exposure to environmental toxicants.

Application of a Physiologically Based Pharmacokinetic Model to Predict Cefazolin and Cefuroxime Disposition in Obese Pregnant Women Undergoing Caesarean Section

“…The physiochemical and pharmacokinetic inputs for the PBPK model of cefazolin are shown in Table 1 [53]. Cefazolin is excreted (approximately 100%) as an unchanged drug in the urine [54].…”

“…The permeability limited kidney model was used to represent the transporters involved in cefazolin clearance. The gestational age-dependent activity of OAT3 was updated in maternal model according to a recent publication as shown in Equation (3) [53],…”

The Use of Pregnancy Physiologically Based Pharmacokinetic Modeling for Renally Cleared Drugs

“…Such quantitative knowledge is being included in ongoing updates of the models. 40,41 Using a newer version (version 20) of the SIMCYP platform, Abduljalil et al 40,41 recently incorporated newly published information of the effect of pregnancy on various renal transporters in pregnancy physiology model. Simulated maternal PK well described observed data for metformin, 40 cefuroxime, and amoxicillin, 41 along with several other drugs.…”

“…40,41 Using a newer version (version 20) of the SIMCYP platform, Abduljalil et al 40,41 recently incorporated newly published information of the effect of pregnancy on various renal transporters in pregnancy physiology model. Simulated maternal PK well described observed data for metformin, 40 cefuroxime, and amoxicillin, 41 along with several other drugs.…”

“…Although beyond the scope of this work, evaluation of medicine use in pregnant women is further complicated by the concern on drug effect to the fetuses PBPK model may be potentially be used to predict fetal exposure to drugs. [40][41][42][43][44] Zhang and Unadkat 43 have developed a maternal-fetal PBPK model to predict fetal exposure for drugs that passively diffuse across the placenta. Other authors 44 showed that the use of perfused placenta technique could be used to enrich PBPK modeling; that is, data from ex vivo experiments could be integrated into PBPK models to study maternal and fetal exposure to drugs used during pregnancy.…”