Pediatric Extrapolation Approach for U.S. Food and Drug Administration Approval of Brexpiprazole in Patients Aged 13 to 17 Years with Schizophrenia

Abstract A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13‐17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure–response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13‐17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model‐based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13‐17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long‐term open‐label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia.