Drug dosing during pregnancy—opportunities for physiologically based pharmacokinetic models

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

Off-label but on evidence?

The Dutch Pediatric Formulary (DPF) provides best evidence-based dosing guidelines for drugs used in children. For each drug-indication-age group combination– together compiling one record we scored the highest available level of evidence: labelled use, systematic review or meta analysis, randomized controlled trial (RCT), comparative research, non-comparative research, or consensus-based expert opinions. For records based on selected guidelines, the original sources were not reviewed. These records were scored as guideline. The file contains 3 sheets: 1. the level of evidence per drug 2. the level of evidence per indication 3: the level of evidence for PK Use the filters in the header row to select drugs, drug groups, age categories or levels of evidence of interest. Drug names and indication names are listed in Dutch