The human mass balance study is a key study in the Clinical Pharmacology package of new drug applications. This study, along with the mass balance studies in toxicology species, provides essential information on the exposure of the parent compound and metabolites. Despite current regulatory guidance and previous publications, a lack of this study, or deficiencies in the study, are still seen in regulatory submissions today. This restricts the assessment of the benefit/risk in all populations and on the potential for drug–drug interactions leading to unnecessary precautions in the label. A review of new drug applications identifies a number of examples of inadequate characterization of circulating drug‐related components or of elimination pathways, with questions raised during the regulatory review. In light of this, new insight is given on what is required from the mass balance study and on how to ensure sufficient information is captured.

Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit–risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions.

Despite the benefits of breastfeeding, lactating mothers who take prescribed medications may discontinue breastfeeding due to concerns associated with infant drug exposure in breastmilk. Consolidating the current knowledge of drug transport to breastmilk may inform understanding of the safety of medication use during lactation. This literature review summarizes the mechanisms of drug transport to breastmilk, details the physicochemical drug properties that may alter the extent of passive transport, and describes the expressional changes in mammary drug transporters that may affect active transport. During the period of 20 July 2023 to 11 August 2023, PubMed® was searched to identify journal articles pertinent to the mechanisms of drug transport from maternal plasma to breastmilk and the expression of mammary drug transporters during lactation. From the 28 studies included in this review, four mechanisms were identified for transporting drugs from maternal plasma to breastmilk: passive transport, active transport, lipid co‐transport, and transcytosis. The lactational expression of 20 drug transporters was further summarized, with 9 transporters demonstrating downregulated expression during lactation and 11 transporters demonstrating upregulated expression during lactation. Understanding the mechanisms of drug transport to breastmilk may aid in estimating infant drug exposure, developing physiologically based pharmacokinetic (PBPK) models that describe drug transfer, and initiating clinical drug development programs in the lactating population.

It is generally recommended that use of medicines should be avoided during pregnancy, sometimes however use of a medicine is essential to safeguard the health of mother and baby. A very limited number of medicines are however specifically licensed for use in pregnancy. This article considers the potential of PBPK modelling as a predictive tool to investigate the expected systemic exposure of medicines in pregnant women and to support possible dosing adjustment to maintain efficacy.

The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed^®, a systematic search was conducted to identify literature relevant to drug metabolism and transport in pregnancy. PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population.