The rational use of PBPK to assess the changing DDI liability in pediatrics: Model qualification and the move towards best practice

Many drug-drug interactions (DDIs) in the pediatric population are managed based on data generated in adults, however this is done with little clinical evidence and the assumption of DDIs being similar between adults and pediatric may not be correct. Physiologically Based Pharmacokinetic models have been used extensively to predict DDIs in adults and this evidence is now being accepted by regulators worldwide and in certain cases information from PBPK is feeding directly into the drug labels. Because pediatric PBPK models account for age related changes in physiology and biochemistry they are ideally placed to extrapolate DDI liability from adults to children. However, marrying together all relevant system factors such as ontogeny of enzymes and hepatic blood flow with drug related factors e.g. extraction ratio and fraction unbound is important and is an active area of research. This review will highlight the need for dynamic rather than static PBPK pediatric DDI predictions with a view to recommending the best practice approach.