Quantitative Extrapolation: An Approach to Validation of Adult Drug Efficacy in Pediatric Subjects

Confirmationofefficacyinpediatricdrugdevelopmenthastraditionallyrequiredlarge,fullypoweredefficacystudiesthathaveproven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic(PD),andclinicaloutcomedatausingpharmacometricmodels,(2)extrapolationusingtheadultpharmacometricmodelto predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials(ie,aquantitativeextrapolationplan).Acasestudyispresentedforquantitativeextrapolationusingdipeptidylpeptidase4(DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.