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

Christoph U Correll,1–3 Rakesh Jain,4 Jonathan M Meyer,5 Antonia Periclou,6 Timothy Carrothers,6 Ágota Barabássy,7 Mehul Patel,8 Willie Earley91Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 2Hofstra Northwell School of M...

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Autores principales:	Correll CU, Jain R, Meyer JM, Periclou A, Carrothers T, Barabássy Á, Patel M, Earley W
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	cariprazine schizophrenia half-life occupancy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/3bc0fd566a5b4a94bbf8de0eca37f36d
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spelling	oai:doaj.org-article:3bc0fd566a5b4a94bbf8de0eca37f36d2021-12-02T03:21:39ZRelationship 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 discontinuation1178-2021https://doaj.org/article/3bc0fd566a5b4a94bbf8de0eca37f36d2019-08-01T00:00:00Zhttps://www.dovepress.com/relationship-between-the-timing-of-relapse-and-plasma-drug-levels-foll-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021Christoph U Correll,1–3 Rakesh Jain,4 Jonathan M Meyer,5 Antonia Periclou,6 Timothy Carrothers,6 Ágota Barabássy,7 Mehul Patel,8 Willie Earley91Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 2Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; 3Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany; 4Texas Tech University School of Medicine – Permian Basin, Department of Psychiatry, Midland, TX, USA; 5University of California, San Diego School of Medicine, Department of Psychiatry, La Jolla, CA, USA; 6Allergan, Department of Clinical Pharmacology, Madison, NJ, USA; 7Department of Medical Affairs, Gedeon Richter Plc, Budapest, Hungary; 8Department of Medical Affairs, Allergan, Madison, NJ, USA; 9Department of Clinical Development, Allergan, Madison, NJ, USACorrespondence: Christoph U CorrellThe Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USATel +1 718 470 4812Email ccorrell@northwell.eduObjective: 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.Keywords: cariprazine, schizophrenia, half-life, occupancyCorrell CUJain RMeyer JMPericlou ACarrothers TBarabássy ÁPatel MEarley WDove Medical Pressarticlecariprazineschizophreniahalf-lifeoccupancyNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol Volume 15, Pp 2537-2550 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	cariprazine schizophrenia half-life occupancy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	cariprazine schizophrenia half-life occupancy Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Correll CU Jain R Meyer JM Periclou A Carrothers T Barabássy Á Patel M Earley W 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
description	Christoph U Correll,1–3 Rakesh Jain,4 Jonathan M Meyer,5 Antonia Periclou,6 Timothy Carrothers,6 Ágota Barabássy,7 Mehul Patel,8 Willie Earley91Department of Psychiatry, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA; 2Hofstra Northwell School of Medicine, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; 3Charité Universitätsmedizin, Department of Child and Adolescent Psychiatry, Berlin, Germany; 4Texas Tech University School of Medicine – Permian Basin, Department of Psychiatry, Midland, TX, USA; 5University of California, San Diego School of Medicine, Department of Psychiatry, La Jolla, CA, USA; 6Allergan, Department of Clinical Pharmacology, Madison, NJ, USA; 7Department of Medical Affairs, Gedeon Richter Plc, Budapest, Hungary; 8Department of Medical Affairs, Allergan, Madison, NJ, USA; 9Department of Clinical Development, Allergan, Madison, NJ, USACorrespondence: Christoph U CorrellThe Zucker Hillside Hospital, Psychiatry Research, 75-59 263rd Street, Glen Oaks, NY 11004, USATel +1 718 470 4812Email ccorrell@northwell.eduObjective: 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.Keywords: cariprazine, schizophrenia, half-life, occupancy
format	article
author	Correll CU Jain R Meyer JM Periclou A Carrothers T Barabássy Á Patel M Earley W
author_facet	Correll CU Jain R Meyer JM Periclou A Carrothers T Barabássy Á Patel M Earley W
author_sort	Correll CU
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/3bc0fd566a5b4a94bbf8de0eca37f36d
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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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