PMID- 28133766
OWN - NLM
STAT- MEDLINE
DCOM- 20180403
LR  - 20210109
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 83
IP  - 7
DP  - 2017 Jul
TI  - Exposure-response analysis after subcutaneous administration of RBP-7000, a 
      once-a-month long-acting Atrigel formulation of risperidone.
PG  - 1476-1498
LID - 10.1111/bcp.13246 [doi]
AB  - 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.
CI  - (c) 2017 The British Pharmacological Society.
FAU - Ivaturi, Vijay
AU  - Ivaturi V
AUID- ORCID: 0000-0002-6433-1154
AD  - Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 
      North Pine Street, Baltimore, MD, 21201, USA.
FAU - Gopalakrishnan, Mathangi
AU  - Gopalakrishnan M
AD  - Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 
      North Pine Street, Baltimore, MD, 21201, USA.
FAU - Gobburu, Jogarao V S
AU  - Gobburu JVS
AD  - Center for Translational Medicine, School of Pharmacy, University of Maryland, 20 
      North Pine Street, Baltimore, MD, 21201, USA.
FAU - Zhang, Weiyan
AU  - Zhang W
AD  - Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
FAU - Liu, Yongzhen
AU  - Liu Y
AD  - Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
FAU - Heidbreder, Christian
AU  - Heidbreder C
AD  - Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
FAU - Laffont, Celine M
AU  - Laffont CM
AD  - Indivior Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA.
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
DEP - 20170331
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Drug Implants)
RN  - 0 (Placebos)
RN  - 34346-01-5 (Polyglactin 910)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
RN  - L6UH7ZF8HC (Risperidone)
RN  - R8P8USM8FR (Paliperidone Palmitate)
SB  - IM
MH  - Absorbable Implants
MH  - Adult
MH  - Antipsychotic Agents/*pharmacology/therapeutic use
MH  - Cytochrome P-450 CYP2D6/*metabolism
MH  - Delayed-Action Preparations/pharmacology/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Drug Delivery Systems
MH  - Drug Implants/pharmacology/therapeutic use
MH  - Female
MH  - Humans
MH  - Injections, Subcutaneous
MH  - Male
MH  - Middle Aged
MH  - Paliperidone Palmitate/*pharmacology
MH  - Placebos
MH  - Polyglactin 910
MH  - Psychiatric Status Rating Scales
MH  - Risperidone/*pharmacology/therapeutic use
MH  - Schizophrenia/*drug therapy
MH  - Treatment Outcome
PMC - PMC5465337
OTO - NOTNLM
OT  - CGI-S
OT  - PANSS
OT  - exposure-response
OT  - long-acting
OT  - pharmacokinetic/pharmacodynamic (PK/PD)
OT  - risperidone
EDAT- 2017/01/31 06:00
MHDA- 2018/04/04 06:00
PMCR- 2018/07/01
CRDT- 2017/01/31 06:00
PHST- 2016/05/10 00:00 [received]
PHST- 2017/01/19 00:00 [revised]
PHST- 2017/01/19 00:00 [accepted]
PHST- 2017/01/31 06:00 [pubmed]
PHST- 2018/04/04 06:00 [medline]
PHST- 2017/01/31 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - BCP13246 [pii]
AID - 10.1111/bcp.13246 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2017 Jul;83(7):1476-1498. doi: 10.1111/bcp.13246. Epub 2017 
      Mar 31.