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.
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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.
SUBMITTER: Correll CU
PROVIDER: S-EPMC6719841 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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