title: Exposure-response analysis after subcutaneous administration of RBP-7000, a once-a-month long-acting Atrigel formulation of risperidone.
abstract: 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.
  
  
  
  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.
  
  
  
  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-1of 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.
  
  
  
  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.
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 North Pine Street, Baltimore, MD, 21201, USA.
authors.forename: Vijay
authors.identifier: 0000-0002-6433-1154
authors.initials: V
authors.lastname: Ivaturi
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 North Pine Street, Baltimore, MD, 21201, USA.
authors.forename: Mathangi
authors.initials: M
authors.lastname: Gopalakrishnan
authors.affiliation: Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 North Pine Street, Baltimore, MD, 21201, USA.
authors.forename: Jogarao V S
authors.initials: JVS
authors.lastname: Gobburu
authors.affiliation: Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
authors.forename: Yongzhen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
authors.affiliation: Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Laffont
mesh_terms: D020341:Absorbable Implants; D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003692:Delayed-Action Preparations / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D004343:Drug Implants / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000494:pharmacology*; D010919:Placebos; D011098:Polyglactin 910; D011569:Psychiatric Status Rating Scales; D018967:Risperidone / Q000494:pharmacology* / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004343:Drug Implants; D010919:Placebos; D011098:Polyglactin 910; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: CGI-S; PANSS; exposure-response; long-acting; pharmacokinetic/pharmacodynamic (PK/PD); risperidone