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      Evaluation of the Highly Variable Agomelatine Pharmacokinetics in Chinese Healthy Subjects to Support Bioequivalence Study

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          Abstract

          Objectives

          We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy.

          Methods

          A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples.

          Results

          The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for C max and AUC 0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%).

          Conclusions

          Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies.

          Trial Registration

          ChiCTR.org ChiCTR-TTRCC-13003835

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          Most cited references12

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          Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration.

          Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.
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            Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials.

            Agomelatine is a novel antidepressant drug with narrative, non-systematic reviews making claims of efficacy. The present study systematically reviewed published and unpublished evidence of the acute and long-term efficacy and acceptability of agomelatine compared with placebo in the treatment of major depression. Randomised controlled trials comparing agomelatine with placebo in the treatment of unipolar major depression were systematically reviewed. Primary outcomes were (a) Hamilton Rating Scale for Depression (HRSD) score at the end of treatment (short-term studies) and (b) number of relapses (long-term studies). Meta-analyses included 10 acute-phase and 3 relapse prevention studies. Seven of the included studies were unpublished. Acute treatment with agomelatine was associated with a statistically significant superiority over placebo of -1.51 HRSD points (99% CI -2.29 to -0.73, nine studies). Data extracted from three relapse prevention studies failed to show significant effects of agomelatine over placebo (relative risk 0.78, 99% CI 0.41-1.48). Secondary efficacy analyses showed a significant advantage of agomelatine over placebo in terms of response (with no effect for remission). None of the negative trials were published and conflicting results between published and unpublished studies were observed. We found evidence suggesting that a clinically important difference between agomelatine and placebo in patients with unipolar major depression is unlikely. There was evidence of substantial publication bias.
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              The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study.

              The present placebo-controlled study evaluated the efficacy, tolerability, and safety of 8-week treatment with agomelatine (25-50 mg/d by mouth) in elderly patients with major depressive disorder (MDD). Elderly outpatients aged ≥ 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD (DSM-IV-TR) were recruited in 27 clinical centers in Argentina, Finland, Mexico, Portugal, and Romania from November 2009 to October 2011. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. A total of 222 elderly patients entered the study (151 in the agomelatine group, 71 in the placebo group), including 69 patients aged 75 years and older. Agomelatine improved depressive symptoms in the elderly population, as evaluated by the HDRS17 total score, in terms of last postbaseline value (agomelatine-placebo difference: mean estimate [standard error] = 2.67 [1.06] points; P = .013) and response to treatment (agomelatine, 59.5%; placebo, 38.6%; P = .004). The agomelatine-placebo difference according to the Clinical Global Impressions-Severity of Illness scale (CGI-S) score was 0.48 (0.19). The agomelatine-placebo difference (estimate [standard error]) for remission on the HDRS17 was 6.9% (4.7%) and did not achieve statistical significance (P = .179, post hoc analysis). Clinically relevant effects of agomelatine were confirmed on all end points in the subset of severely depressed patients (HDRS17 total score ≥ 25 and CGI-S score ≥ 5 at baseline). Agomelatine was well tolerated by patients, with only minimal distinctions from placebo. The present study provides the first evidence that an 8-week treatment with agomelatine 25-50 mg/d efficiently relieves depressive symptoms and is well tolerated in elderly depressed patients older than 65 years. Controlled-Trials.com identifier: ISRCTN57507360. © Copyright 2011 Physicians Postgraduate Press, Inc.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                20 October 2014
                : 9
                : 10
                : e109300
                Affiliations
                [1 ]Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
                [2 ]Department of pharmacy, Changde First People's Hospital, Changde, Hunan, China
                [3 ]Department of pharmacy, the Third Xiangya Hospital, Central South University, Changsha, Hunan, China
                [4 ]Department of Clinical Pharmacy, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America
                Penn State College of Medicine, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GPY QP. Performed the experiments: YW RRZ LH. Analyzed the data: YW QP RRZ LH. Contributed reagents/materials/analysis tools: HYT CXG YXX JH. Wrote the paper: YW QP. Involved in the modification of the manuscript: ZYH SKL HY.

                Article
                PONE-D-13-46509
                10.1371/journal.pone.0109300
                4203722
                25330096
                a31850a5-8f55-4a3d-b7ae-2b9e97959545
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 January 2014
                : 25 August 2014
                Page count
                Pages: 7
                Funding
                This work was supported by the National Scientific Foundation of China (No. 81373476, 81302851, 81301924, URL: http://www.nsfc.gov.cn), the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2012ZX09303014-001, URL: http://www.nmp.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Clinical Medicine
                Pharmacology
                Clinical Pharmacology
                Drug Information

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