Relationship between the timing of relapse and plasma drug levels following discontinuation of cariprazine treatment in patients with schizophrenia: indirect comparison with other second-generation antipsychotics after treatment discontinuation.

Abstract

OBJECTIVE:

To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs).

METHODS:

Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan-Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves.

RESULTS:

The Kaplan-Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6-7 weeks after randomization, compared to the Kaplan-Meier curves for the other AAPs, which showed earlier separation at 1-4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8-34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2-4 weeks after last dose.

CONCLUSION:

Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.

• Authors: Christoph U Correll, Rakesh Jain, Jonathan M Meyer, Antonia Periclou, Timothy Carrothers, Ágota Barabássy, Mehul Patel, Willie Earley
• Journal: Neuropsychiatric disease and treatment (Neuropsychiatr Dis Treat) Vol. 15 Pg. 2537-2550 ( 2019) ISSN: 1176-6328 [Print] New Zealand
• PMID: 31507322 (Publication Type: Journal Article)