Extrapolating Efficacy of Cariprazine to Pediatric Schizophrenia and Bipolar Mania Through Population Pharmacokinetic Analysis.

The US FDA recently accepted efficacy extrapolation from adult to pediatric patients for atypical antipsychotics in the treatment of schizophrenia (SCZ) and bipolar mania (BPM), considering the similarity in both disease and exposure-response relationships for this class of drugs. Under this pharmacokinetic (PK)-based efficacy extrapolation framework, pediatric population PK (popPK) models for cariprazine and its two active metabolites (desmethyl cariprazine [DCAR], didesmethyl cariprazine [DDCAR]) were developed by modifying previously validated adult popPK models and using pediatric PK data from two phase I trials. Covariate effects on PK parameters in legacy adult models were retained in the pediatric models, except that body weight effect on apparent elimination clearance and apparent volume of distribution of the central compartment were re-estimated for all analytes. The final pediatric popPK models adequately described observed plasma concentrations of all three analytes with no significant bias over age or body weight in pediatric patients. Simulated total cariprazine (sum of cariprazine, DCAR and DDCAR) exposure at 1.5-4.5 mg once daily (QD) in adolescents (13-17 years) with SCZ and 3.0-4.5 mg QD in children (10-12 years) and adolescents with BPM resulted in predicted total cariprazine exposures within established efficacious ranges in adults with these conditions. Body weight did not meaningfully affect total cariprazine exposure and analyses did not support weight-based dosing in 10-12 year olds. This PK analysis supported the FDA approvals of cariprazine for the treatment of SCZ and BPM in pediatric patients by identifying efficacious doses for each indication based on efficacy extrapolation.