Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment)

Tadakatsu Nakamura,1 Tomoko Kubota,1 Atsushi Iwakaji,1 Masayoshi Imada,1 Margit Kapás,2 Yasunori Morio1 1Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 2Developmental Drug Metabolism and Pharmacokinetics, Gedeon Richter Plc, Budapest, Hungary Purpose: Cariprazine is a potent dopamine D3-preferring D3/D2 receptor partial agonist in development for the treatment of schizophrenia, bipolar mania, and depression. Pharmacokinetics of cariprazine and the two clinically relevant metabolites (desmethyl- and didesmethyl-cariprazine) was evaluated in a clinical pharmacology study. Methods: This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (≤4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed. Results: Steady state was reached within 1–2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased ~50% at 1 week, and total active moieties decreased ~90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was ~1 week. Incidence of treatment-emergent adverse events was 97.4%; 15.8% of patients discontinued due to adverse events. No abnormal laboratory values or major differences from baseline in extrapyramidal symptoms were observed. Conclusion: Cariprazine and its active metabolites reached steady state within 4 weeks, and exposure was dose proportional over the range of 3–9 mg/day. Once-daily cariprazine was generally well tolerated in adult patients with schizophrenia. Keywords: schizophrenia, cariprazine, pharmacokinetics, desmethyl-cariprazine, didesmethyl-cariprazin