Pediatric Drug-Drug Interaction Evaluation: Drug, Patient Population, and Methodological Considerations.

Hospitalized pediatric patients and those with complex or chronic conditions treated on an outpatient basis are commonly prescribed multiple drugs, resulting in increased risk for drug-drug interactions (DDIs). Although dedicated DDI evaluations are routinely performed in healthy adult volunteers during drug development, they are rarely performed in pediatric patients because of ethical, logistical, and methodological challenges. In the absence of pediatric DDI evaluations, adult DDI data are often extrapolated to pediatric patients. However, the magnitude of a DDI in pediatric patients may differ from adults because of age-dependent physiological changes that can impact drug disposition or response and because of other factors related to the drug (eg, dose, formulation) and the patient population (eg, disease state, obesity). Therefore, the DDI magnitude needs to be assessed in children separately from adults, although a lack of clinical DDI data in pediatric populations makes this evaluation challenging. As a result, pediatric DDI assessment relies on the predictive performance of the pharmacometric approaches used, such as population and physiologically based pharmacokinetic modeling. Therefore, careful consideration needs to be given to adequately account for the age-dependent physiological changes in these models to build high confidence for such untested DDI scenarios. This review article summarizes the key considerations related to the drug, patient population, and methodology, and how they can impact DDI evaluation in the pediatric population.