Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

Abstract

Drugs can have harmful effects on the embryo or the 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 non-pregnant 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. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed.

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Acknowledgements

The authors thank Jessica Waite and Anna Kenworthy for their assistance with collecting the references and preparing the manuscript. The authors also thank Ruth Clayton for helpful comments and proofreading and the reviewers of this manuscript for helpful suggestions and comments.

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Abduljalil, K., Badhan, R.K.S. Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models. J Pharmacokinet Pharmacodyn (2020). https://doi.org/10.1007/s10928-020-09698-w

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Keywords

  • Pregnancy
  • Physiologically-based pharmacokinetic model
  • Dosing adjustment
  • Fetal exposure