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

Abstract

PurposeCariprazine 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.MethodsThis 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.ResultsSteady 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.ConclusionCariprazine 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.

Quality-adjusted life year difference in patients with predominant negative symptoms of schizophrenia treated with cariprazine and risperidone

“…Considering the pharmacokinetic properties of cariprazine [10][11][12], transition probabilities and clinical efficacy in the first 4-6 weeks of cariprazine treatment may not be fully representative for the consecutive time period. In accordance with this, the model was constructed with weekly cycles in the initial 6-week time period and 12-week long cycles for the latter periods, therefore the use of different transition probabilities was necessary for the first 6 weeks and for the subsequent model time period.…”

Current Data on and Clinical Insights into the Treatment of First Episode Nonaffective Psychosis: A Comprehensive Review

“…Initial animal studies with cariprazine, a potent D3/D2 receptor partial agonist with favored binding to D3 receptors, seem to point out it could be a better treatment option for patients with persistent and predominant negative symptoms [180]. The long half-life of cariprazine’s principal active metabolites and the steady-state levels of cariprazine and metabolites within 4 weeks are pharmacological characteristics that may minimize the impact of missing doses on plasma levels [181]. Significant improvement in hostility has been also observed in cariprazine- versus placebo-treated patients [182].…”

Relationship Between Plasma Concentrations and Clinical Effects of Cariprazine in Patients With Schizophrenia or Bipolar Mania

“…As such, the additive shift for the Asian race in the YMRS models was obtained from studies conducted in India and may not be reflective of patients from other geographic regions in Asia. Race did not seem to have a substantial effect on PK . Subgroup analyses from clinical efficacy studies did not distinguish any efficacy difference based on race or geographic region…”

“…DDCAR are pharmacologically equipotent to cariprazine. 6 Steady-state levels of cariprazine and DCAR can be reached within 1-2 weeks and reached for DDCAR within 4 weeks. Steady-state exposure for DDCAR is 2-3 times higher than cariprazine, whereas DCAR is 30-40% of carprazine exposure.…”

“…Cariprazine also acts as an antagonist at 5‐HT 2B receptors, with lower affinity for 5‐HT 2A , 5‐HT 2C , histamine H 1 , and adrenergic α 1 receptors and negligible affinity for other receptors (e.g., cholinergic muscarinic receptors) . Two major metabolites, desmethyl‐cariprazine (DCAR) and didesmethyl‐cariprazine (DDCAR), are formed from cariprazine, and both DCAR and DDCAR are pharmacologically equipotent to cariprazine . Steady‐state levels of cariprazine and DCAR can be reached within 1–2 weeks and reached for DDCAR within 4 weeks.…”