Maternal-Fetal Pharmacology of Drugs: A Review of Current Status of the Application of Physiologically Based Pharmacokinetic Models

Abstract

Pregnancy and the postpartum period are associated with several physiological changes that can alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. For certain drugs, dosing changes may be required during pregnancy and postpartum to achieve drug exposures comparable to what is observed in non-pregnant subjects. There is very limited data on fetal exposure of drugs during pregnancy, and neonatal exposure through transfer of drugs via human milk during breastfeeding. Very few systematic clinical pharmacology studies have been conducted in pregnant and postpartum women due to ethical issues, concern for the fetus safety as well as potential legal ramifications. Over the past several years, there has been an increase in the application of modeling and simulation approaches such as population PK (PopPK) and physiologically based PK (PBPK) modeling to provide guidance on drug dosing in those special patient populations. Population PK models rely on measured PK data, whereas physiologically based PK models incorporate physiological, preclinical, and clinical data into the model to predict drug exposure during pregnancy. These modeling strategies offer a promising approach to identify the drugs with PK changes during pregnancy to guide dose optimization in pregnancy, when there is lack of clinical data. PBPK modeling is also utilized to predict the fetal exposure of drugs and drug transfer via human milk following maternal exposure. This review focuses on the current status of the application of PBPK modeling to predict maternal and fetal exposure of drugs and thereby guide drug therapy during pregnancy.

Foetal and neonatal exposure prediction and dosing evaluation for ampicillin using a physiologically‐based pharmacokinetic modelling approach

“…Owing to their physiologically‐based structure, PBPK models are particularly useful for predicting changes in a drug's PKs as a function of age by incorporating the known growth changes and maturation in processes that affect the absorption, distribution, metabolism and excretion (ADME) of a drug 17 . In addition, with consideration of the placental kinetics and detailed changes in maternal and foetal physiological and biochemical parameters, the pregnancy (maternal‐placental‐foetal) PBPK model is a suitable tool to facilitate the assessment of foetal exposure 18 . The use of PBPK models for prediction of drug exposure at different age groups in paediatric populations have been widely described, 17,19 and recently there has been a growing interest in the prediction of foetal drug exposures using the pregnancy PBPK model 20,21 …”

“…17 In addition, with consideration of the placental kinetics and detailed changes in maternal and foetal physiological and biochemical parameters, the pregnancy (maternal-placental-foetal) PBPK model is a suitable tool to facilitate the assessment of foetal exposure. 18 The use of PBPK models for prediction of drug exposure at different age groups in paediatric populations have been widely described, 17,19 and recently there has been a growing interest in the prediction of foetal drug exposures using the pregnancy PBPK model. 20,21 The goal of this study was twofold: (1) to apply a PBPK modelling approach to characterize the disposition of ampicillin in foetuses during the intrapartum period and in neonates, and (2) to evaluate recommended ampicillin dosing in these two vulnerable populations.…”

Pharmacotherapy during Pregnancy, Childbirth, and Lactation

“…Compared to classic non-compartmental analyses, analyses applying either population pharmacokinetic modeling or physiologically based pharmacokinetic (PBPK) modeling are much more advanced, while PBPK can also inform us about placental and fetal exposure [ 3 ]. We refer interested readers to some recent reviews on this topic [ 4 , 5 , 6 ].…”

Fetal Clinical Pharmacology: A New Frontier of Drug Safety and Therapeutics

“…In parallel, the number of pregnancy PBPK models used to simulate both maternal and fetal PK is continuously increasing, 12 adding to the knowledge base of in silico models for placental drug transfer. In view of the limited extrapolatability of animal data to humans and the difficulties in obtaining in vivo samples from the fetus, PBPK models could be leveraged to refine our knowledge about fetal PK 9,13 . Being (semi)mechanistic in nature, these models could also be used in the future to scale the PK in utero to earlier stages of gestation, thereby providing a first estimate for the magnitude of embryonic or fetal drug exposure, which could ultimately feed into investigations of a drug's pharmacodynamics (PD) and its teratogenic risk.…”

“…In view of the limited extrapolatability of animal data to humans and the difficulties in obtaining in vivo samples from the fetus, PBPK models could be leveraged to refine our knowledge about fetal PK. 9,13 Being (semi)mechanistic in nature, these models could also be used in the future to scale the PK in utero to earlier stages of gestation, thereby providing a first estimate for the magnitude of embryonic or fetal drug exposure, which could ultimately feed into investigations of a drug's pharmacodynamics (PD) and its teratogenic risk. Therefore, however, a sound understanding of the PK/PD relationship in the developing fetus is indispensable.…”