Pharmacokinetics, Safety, and Tolerability of Cariprazine in Pediatric Patients with Bipolar I Disorder or Schizophrenia

Objective: Cariprazine is a dopamine D 3 -preferring D 3 /D 2 and serotonin 5-HT 1A receptor partial agonist approved to treat adults with schizophrenia and manic/mixed or depressive episodes associated with bipolar I disorder. This sequential-cohort, dose-escalation study was the first to evaluate the pharmacokinetic, safety, and tolerability profile of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), in pediatric patients with schizophrenia or bipolar I disorder. Methods: This phase I open-label study enrolled patients with schizophrenia (13–17 years of age) or bipolar I disorder (10–17 years of age). Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for schizophrenia or bipolar I disorder and had Positive and Negative Syndrome Scale (PANSS) total scores ≥70 or Young Mania Rating Scale (YMRS) total scores ≥20. Patients were assigned to one of four treatment groups to receive 6 weeks of cariprazine treatment through slow titration to 1.5, 3, or 4.5 mg/d or fast titration to 4.5 mg/d. Pharmacokinetics, adverse events (AEs), and various safety parameters were analyzed. Efficacy was evaluated as an exploratory outcome. Results: A total of 50 participants were enrolled. Based on mean trough levels, steady state appeared to be reached within 1–2 weeks for cariprazine and DCAR and within 4–5 weeks for DDCAR. Systemic exposure of cariprazine, DCAR, and DDCAR generally increased approximately in proportion to the increases in dose from 1.5 to 4.5 mg/d. The most frequent treatment-related, treatment-emergent AEs included sedation, parkinsonism, tremor, dystonia, and blurred vision. Improvements from baseline on the PANSS and YMRS were observed throughout treatment. Conclusion: In this first investigation of cariprazine in a pediatric population with schizophrenia or bipolar disorder, pharmacokinetic parameters were consistent with those observed in adults. Cariprazine appeared to be safe and tolerable in children and adolescents.