Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Abstract

Drugs can have harmful effects on the embryo or fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of nonpregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester.This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions.For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Three examples were described to show how pregnancy PBPK can facilitate and guide dose assessment throughout gestation.

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

“…A recent review of PBPK models used for pregnant women demonstrated that in a vast majority of cases, only the maternal Cp time profile prediction was investigated, justifying a simplified model structure. Only a few cases were also interested in fetal blood cord exposure [52]. Therefore, as an initial step, a simplified fetal PBPK model was created as data were available to perform multiple validation cases study.…”

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study

“…However, the metabolic breakdown of sertraline is complicated, and includes CYPs 2B6, 2C9, 2C19, 2D6, and 3A4. The contribution of each isozyme has proven difficult to determine in vivo; however, the variable up‐ or downregulation of CYP isozyme expression during gestation (Abduljalil & Badhan, 2020) may contribute to the disparity observed in some studies (Westin et al., 2017). For example, the approximate 2‐fold decrease in 2C19 activity coupled with approximately 2‐fold increase in 2B6 activity by trimester 3 may negate the overall impact of each pathway, in preference to changes in other physiological factors such as increases in total body water.…”

Role of Physiologically Based Pharmacokinetic Modeling and Simulation in Enabling Model‐Informed Development of Drugs and Biotherapeutics

“…21,22 Pregnant women are generally not enrolled in trials because of possible risks to the fetus; hence, PBPK offers a unique predictive tool to combine physicochemical and available pharmacokinetic data and gestational-age-dependent changes in patient physiology to quantitively predict the changes in pharmacokinetics of drugs during pregnancy. 23,24 Chaphekar et al describe the physiological changes during pregnancy and how such changes may impact the pharmacokinetics of drugs. 25 In addition, they discuss the application of various PBPK models to not only predict the pharmacokinetics of drugs in various trimesters of pregnancy but also fetal exposures.…”

“…A multitude of physiological and metabolic changes occur during pregnancy 21,22 . Pregnant women are generally not enrolled in trials because of possible risks to the fetus; hence, PBPK offers a unique predictive tool to combine physicochemical and available pharmacokinetic data and gestational‐age‐dependent changes in patient physiology to quantitively predict the changes in pharmacokinetics of drugs during pregnancy 23,24 . Chaphekar et al describe the physiological changes during pregnancy and how such changes may impact the pharmacokinetics of drugs 25 .…”