Population Pharmacokinetic Analysis of Brexpiprazole to Support its Indication and Dose Selection in Adolescents With Schizophrenia

Abstract

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off‐label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose–exposure between adults and adolescents aged 13‐17 years following oral daily doses of brexpiprazole 1‐4 mg, indicating that the target brexpiprazole dose of 2‐4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13‐17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents.

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

“…The Applicant asserts that the study protocols were approved by the Institutional Review Board or Independent Ethics Committee at each respective trial center. 10 Consistent with ethical principles for the protection of human research subjects, no trial procedures were performed on trial candidates until written consent or assent had been obtained from them and/or their legally acceptable representative.…”

“…The details of the applicant's PK model are available elsewhere. 10 Briefly, the PK of brexpiprazole was best described by a twocompartment model with sequential zero-first-order absorption and linear elimination. The PK model had clearance and volume of distribution allometrically scaled by body weight (raised to the power of 0.75 for clearance, and 1 for volume of distribution).…”