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      Exposure‐response analysis after subcutaneous administration of RBP‐7000, a once‐a‐month long‐acting Atrigel formulation of risperidone

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          Abstract

          Aims

          A new, long‐acting, subcutaneous (SC) formulation of risperidone (RBP‐7000) has been developed for the treatment of schizophrenia to address issues of non‐adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure‐response relationship between total active moiety (AM) plasma exposure (risperidone + 9‐hydroxy‐risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impression severity (CGI‐S) scores using data from a registration trial.

          Methods

          This was a Phase 3 randomized, double‐blind, placebo‐controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP‐7000 (90 mg and 120 mg). Non‐linear mixed effects modelling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9‐hydroxy‐risperidone with placebo and drug‐effect models to establish the relation between total AM exposure and PANSS or CGI‐S scores.

          Results

          CYP2D6 poor and intermediate metabolizers had lower formation rates of 9‐hydroxy‐risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo‐corrected relative decrease in PANSS score from baseline following RBP‐7000 treatment was 5.4%, half of which could be achieved at plasma concentrations of 4.6 ng ml −1 of the total AM. A proportional odds model for the CGI‐S score related the total AM plasma concentration to the probability of improving/worsening scores over time.

          Conclusions

          Exposure‐response analysis was established between total AM concentrations and PANSS and CGI‐S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.

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          Author and article information

          Contributors
          celine.laffont@Indivior.com
          Journal
          Br J Clin Pharmacol
          Br J Clin Pharmacol
          10.1111/(ISSN)1365-2125
          BCP
          British Journal of Clinical Pharmacology
          John Wiley and Sons Inc. (Hoboken )
          0306-5251
          1365-2125
          31 March 2017
          July 2017
          : 83
          : 7 ( doiID: 10.1111/bcp.v83.7 )
          : 1476-1498
          Affiliations
          [ 1 ] Center for Translational Medicine, School of Pharmacy University of Maryland 20 North Pine Street Baltimore MD 21201 USA
          [ 2 ] Indivior Inc. 10710 Midlothian Turnpike, Suite 430 Richmond VA 23235 USA
          Author notes
          [* ] Correspondence

          Dr Celine Laffont, Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA 23235, USA.

          Tel.: +1 804 594 1882

          Fax: +1 804 423 8952;

          E‐mail: celine.laffont@ 123456indivior.com

          Article
          PMC5465337 PMC5465337 5465337 BCP13246 MP-00380-16.R3
          10.1111/bcp.13246
          5465337
          28133766
          © 2017 The British Pharmacological Society
          Page count
          Figures: 19, Tables: 6, Pages: 23, Words: 8361
          Funding
          Funded by: Indivior Inc.
          Award ID: Research Contract Agreement with University of Mar
          Categories
          Pharmacokinetic Dynamic Relationships
          Pharmacokinetic Dynamic Relationships
          Custom metadata
          2.0
          bcp13246
          July 2017
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.1 mode:remove_FC converted:09.06.2017

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