Sunny Chapel1, Yu-Yuan Chiu2, Jay Hsu3, Josephine Cucchiaro3, Antony Loebel3. 1. Ann Arbor Pharmacometrics Group Inc, Ann Arbor, Michigan. 2. Sunovion Pharmaceuticals Inc, Fort Lee, New Jersey. Electronic address: yu-yuan.chiu@sunovion.com. 3. Sunovion Pharmaceuticals Inc, Fort Lee, New Jersey.
Abstract
PURPOSE: Characterization of dose-response relationships for psychotropic agents may be difficult to determine based on results of individual clinical studies, particularly those with a flexible dose design. The goal of this pharmacometric analysis was to characterize the dose-response profile for lurasidone in patients with bipolar depression. METHODS: The statistical modeling and simulation analyses reported here were derived from 2 randomized, 6-week, double-blind, placebo-controlled, flexible-dose studies (20-60 mg/d or 80-120 mg/d of lurasidone as monotherapy or 20-120 mg/d adjunct to lithium or valproate) in patients with bipolar depression. Pooled data included 5245 Montgomery-Åsberg Depression Rating Scale (MADRS) observations from 825 patients who had receivedlurasidone or placebo treatments, with or without lithium or valproate background medication. FINDINGS: The time course of placebo effect on the MADRS score was adequately described by an exponential asymptotic placebo model. A linear dose-response model best described the effect of lurasidone. The net improvement in MADRS score due to lurasidone treatment (the drug effect) was significant (P < 0.001), and a positive dose response was detected. Net drug effect after 6 weeks of treatment was estimated to be a 6.0-point decrease in MADRS score per 100 mg of lurasidone. Covariate effects (for age and lithium or valproate use) were significant only for placebo effect parameters; thus, no dose adjustment was necessary related to demographic covariates. IMPLICATIONS: This population dose-response modeling analysis indicates that higher doses of lurasidone are likely to produce greater therapeutic effects in patients with bipolar depression. The linear dose response was consistent for both lurasidone monotherapy and adjunctive therapy in patients with bipolar depression. ClinicalTrials.gov identifiers: NCT00868452, NCT00868699.
RCT Entities:
PURPOSE: Characterization of dose-response relationships for psychotropic agents may be difficult to determine based on results of individual clinical studies, particularly those with a flexible dose design. The goal of this pharmacometric analysis was to characterize the dose-response profile for lurasidone in patients with bipolar depression. METHODS: The statistical modeling and simulation analyses reported here were derived from 2 randomized, 6-week, double-blind, placebo-controlled, flexible-dose studies (20-60 mg/d or 80-120 mg/d of lurasidone as monotherapy or 20-120 mg/d adjunct to lithium or valproate) in patients with bipolar depression. Pooled data included 5245 Montgomery-Åsberg Depression Rating Scale (MADRS) observations from 825 patients who had received lurasidone or placebo treatments, with or without lithium or valproate background medication. FINDINGS: The time course of placebo effect on the MADRS score was adequately described by an exponential asymptotic placebo model. A linear dose-response model best described the effect of lurasidone. The net improvement in MADRS score due to lurasidone treatment (the drug effect) was significant (P < 0.001), and a positive dose response was detected. Net drug effect after 6 weeks of treatment was estimated to be a 6.0-point decrease in MADRS score per 100 mg of lurasidone. Covariate effects (for age and lithium or valproate use) were significant only for placebo effect parameters; thus, no dose adjustment was necessary related to demographic covariates. IMPLICATIONS: This population dose-response modeling analysis indicates that higher doses of lurasidone are likely to produce greater therapeutic effects in patients with bipolar depression. The linear dose response was consistent for both lurasidone monotherapy and adjunctive therapy in patients with bipolar depression. ClinicalTrials.gov identifiers: NCT00868452, NCT00868699.
Authors: Konstantinos N Fountoulakis; Lakshmi Yatham; Heinz Grunze; Eduard Vieta; Allan Young; Pierre Blier; Siegfried Kasper; Hans Jurgen Moeller Journal: Int J Neuropsychopharmacol Date: 2017-02-01 Impact factor: 5.176