Cariprazine is metabolized primarily by cytochrome P450 (CYP) 3A4. It is a weak inhibitor of CYP2D6 and CYP3A4.1 Hepatic metabolism of cariprazine produces 2 active metabolites: desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), both of which are equipotent to cariprazine. After multiple dose administration, mean cariprazine and DCAR levels reach steady state in 1 to 2 weeks; DDCAR, in 4 to 8 weeks. The systemic exposure and serum levels of DDCAR are roughly 3-fold greater than cariprazine because of the longer elimination half-life of DDCAR.1
Efficacy in schizophrenia
The efficacy of cariprazine in schizophrenia was established by 3 six-week, randomized, placebo-controlled trials. Two trials were fixed-dosage; a third used 2 flexible dosage ranges. The primary efficacy measure was change from baseline in the total score of the PANSS at the end of Week 6, compared with placebo. In all trials, patients were adults (age 18 to 60) who met DSM-IV-TR criteria for schizophrenia and had a PANSS score between 80 and 120 at screening and baseline.
Study 1 (n = 711) compared dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d with placebo.7 All cariprazine dosages and an active control (risperdone) were superior to placebo in reducing symptoms of schizophrenia, as measured by the PANSS. The placebo-subtracted differences on PANSS score at 6 weeks for dosages of 1.5 mg/d, 3 mg/d, and 4.5 mg/d were –7.6, –8.8, –10.4, respectively (significant at 95% CI).
Study 2 (n = 151) compared 3 mg/d and 6 mg/d dosages of cariprazine with placebo.1 Both dosages and an active control (aripiprazole) were superior to placebo in reducing PANSS scores. Placebo-subtracted differences on PANSS score at 6 weeks for dosages of 3 mg/d and 6 mg/day were –6.0, –8.8, respectively (significant at 95% CI).
Study 3 (n = 147) was a fixed-flexible dosage trial comparing cariprazine, 3 to 6 mg/d and 6 to 9 mg/d dosage ranges, to placebo.8 Both ranges were superior to placebo in reducing symptoms on PANSS. Placebo-subtracted differences from placebo on PANSS at 6 weeks for cariprazine 3 to 6 or 6 to 9 mg/d were –6.8, –9.9, respectively (significant at 95% CI).
These trials established the efficacy of cariprazine for acute schizophrenia at dosages ranging from 1.5 to 9 mg/d. Although there was a modest trend toward higher efficacy at higher dosages, there was a dose-related increase in certain adverse reactions (extrapyramidal symptoms [EPS]) at dosages >6 mg/d.1
Efficacy in bipolar disorder
The efficacy of cariprazine for acute treatment of manic or mixed episodes of BD I was established in 3 randomized, placebo-controlled, flexibly dosed 3-week trials. In all trials, patients were adults (age 18 to 65) who met DSM-IV-TR criteria for BD I with manic or mixed episodes and with or without psychotic features (YMRS score, ≥20). The primary efficacy measure in the 3 trials was a change from baseline in the total YMRS score at the end of Week 3, compared with placebo.
Study 1 (n = 492) compared 2 flexibly dosed ranges of cariprazine (3 to 6 mg/d and 6 to 12 mg/d) with placebo.10 Both dosage ranges were superior to placebo in reducing mixed and manic symptoms, as measured by reduction in the total YMRS score. Placebo-subtracted differences in YMRS scores from placebo at Week 3 for cariprazine 3 to 6 mg/d and 6 to 12 mg/d were –6.1, –5.9, respectively (significant at 95% CI). The higher range offered no additional advantage over the lower range.
Study 2 (n = 235) compared flexibly dosed cariprazine, 3 to 12 mg/d, to placebo.11 Cariprazine was superior to placebo in reducing bipolar symptoms as measured by the YMRS. The difference between cariprazine 3 to 12 mg/d and placebo on the YMRS score at Week 3 was –6.1 (significant at 95% CI).
Study 3 (n = 310) compared flexibly dosed cariprazine, 3 to 12 mg/d, with placebo.15 Again, cariprazine was superior to placebo in reducing the YMRS score at Week 3: difference, –4.3 (significant at 95% CI).
These trials establish the efficacy of cariprazine in treating acute mania or mixed BD I episodes at dosages ranging from 3 to 12 mg/d. Dosages >6 mg/d did not offer additional benefit over lower dosages, and resulted in a dosage-related increase in EPS at dosages >6 mg/d.16
Tolerability
Cariprazine generally was well tolerated in short-term trials for schizophrenia and BD I. The only treatment-emergent adverse event reported for at least 1 treatment group in all trials at a rate of ≥10%, and at least twice the rate seen with placebo was akathisia. Adverse events reported at a lower rate than placebo included EPS (particularly parkinsonism), restlessness, headache, insomnia, fatigue, and gastrointestinal distress. The discontinuation rate due to AEs for treatment groups and placebo-treated patients generally was similar. In schizophrenia Study 3, for example, the discontinuation rate due to AEs was 13% for placebo; 14% for cariprazine, 3 to 6 mg/d; and 13% for cariprazine, 6 to 9 mg/d.1 48-Week open-label safety study. Patients with schizophrenia received open-label cariprazine for as long as 48 weeks.7 Serious adverse events were reported in 12.9%, including 1 death (suicide); exacerbation of symptoms of schizophrenia (4.3%); and psychosis (2.2%). Treatment-emergent adverse events reported in at least 10% of patients included akathisia (14.0%), insomnia (14.0%), and weight gain (11.8%). The mean change in laboratory values, blood pressure, pulse rate, and electrocardiographic parameters was clinically insignificant.