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

Using Current Evidence in Selecting Antiepileptic Drugs for Use During Pregnancy

Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of fetal anticonvulsant syndrome. Accepted treatment paradigms to minimize fetal risks include use of AED monotherapy and folic acid supplementation. However, as data are acquired from several ongoing pregnancy registries, differential risks among the various AED monotherapy regimens are being defined, further improving fetal outcomes

Intraventricular pentosan polysulphate in human prion disease: An observational study in the UK

Background, purpose and methods: This observational study assessed the effect of continuous intraventricular infusion of pentosan polysulphate (PPS) in seven patients at different clinical centres in the UK. Results: Complications of intraventricular catheterization were frequent. PPS was well-tolerated over a wide dose range (11-110 mu g/kg/day) during the 6-month study. Four patients were assessed for the entire study period: one remained stable, two showed minimal deterioration and one progressed significantly. Conclusion: Mean survival of all patients was longer than reported values for natural history of specific prion disorders. Possible reasons for these findings are explored