Development of an Empirical Approach for the Prediction of Cytochrome P450-Based Drug-Drug Interactions in Pediatric...

Background and Objective: Predicting drug-drug interactions (DDIs) in pediatric patients remains a major challenge in clinical pharmacology. This study aimed to evaluate and compare three empirical approaches for extrapolating adult cytochrome P450 (CYP)-mediated DDI pharmacokinetics (PK) data to predict the extent of the corresponding DDIs in children across different age groups. Methods: The approaches assessed were: (A) the direct use of adult area under the plasma concentration-time curve ratios (AUCRs) as estimators of pediatric values; (B) the application of a correction accounting for the ontogeny of the involved CYP enzyme; and (C) the application of corrections for both enzyme ontogeny and allometric scaling. Twenty-five pediatric AUCRs were predicted from adult AUCR data. Predictive performance was evaluated by comparing predicted AUCR_pediatric values with observed values, using a 50-200% acceptability range. Results: Approach C demonstrated superior predictive capability, with only one out of 25 predictions falling outside the acceptability range. In contrast, both approaches A and B resulted in three values each outside this range. Further visual exploration and detailed performance analyses confirmed the enhanced accuracy of approach C in predicting pediatric DDIs compared with the other approaches. Conclusions: This study demonstrates that the proposed approach of considering both ontogeny and allometric scaling represents a robust and reasonable method to anticipate the extent of pediatric CYP-based DDIs when adult PK data are available.