title: Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment).
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Tadakatsu
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwakaji
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Imada
authors.affiliation: Developmental Drug Metabolism and Pharmacokinetics, Gedeon Richter Plc, Budapest, Hungary.
authors.forename: Margit
authors.initials: M
authors.lastname: Kapás
authors.affiliation: Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Morio
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; C000611434:desmethylcariprazine; C000611435:didesmethylcariprazine; C533287:cariprazine
keywords: cariprazine; desmethyl-cariprazine; didesmethyl-cariprazine; pharmacokinetics; schizophrenia
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