Pimavanserin Exposure-Response Analyses in Patients With Schizophrenia: Results From the Phase 2 ADVANCE Study

Mona Darwish, Dragana Bugarski-Kirola, Julie Passarell, Joel Owen, David Jaworowicz, Daryl DeKarske, Srdjan Stankovic, Mona Darwish, Dragana Bugarski-Kirola, Julie Passarell, Joel Owen, David Jaworowicz, Daryl DeKarske, Srdjan Stankovic

Abstract

Purpose/background: Pimavanserin is a selective serotonin 5-HT 2A receptor inverse agonist/antagonist being investigated in patients with negative symptoms of schizophrenia. This analysis aimed to characterize exposure-response relationships of pimavanserin in this population.

Methods/procedures: Exposure-response models were developed using data from ADVANCE. Patients with negative symptoms of schizophrenia receiving background antipsychotics were randomized to pimavanserin 20 mg (adjusted to 34 or 10 mg between weeks 2-8 based on efficacy or tolerability) or placebo for 26 weeks. Time-varying pimavanserin exposure measures were predicted for each patient using a population pharmacokinetic model and individual empiric Bayesian parameter estimates. Response measures were the Negative Symptom Assessment 16 (NSA-16, primary end point), Personal and Social Performance scale, negative symptoms component of the Clinical Global Impression of Schizophrenia-Severity Scale, and adverse events.

Findings/results: A higher pimavanserin exposure was associated with greater improvement in NSA-16 score. For a median area under the pimavanserin plasma concentration-time curve from time 0 to 24 hours of 1465 ng × h/mL for the 34-mg dose, the model predicted a 10.5-point reduction in NSA-16 score. This exposure-response relationship with NSA-16 scores was not influenced by covariates. Similar results were observed with Personal and Social Performance and Clinical Global Impression of Schizophrenia-Severity, but not to the extent as NSA-16. There was no significant exposure-response relationship with anxiety, headache, insomnia, or somnolence.

Implications/conclusions: Increasing pimavanserin plasma concentration was associated with improved NSA-16 scores (primary end point) in patients with negative symptoms of schizophrenia. No exposure-response relationship with select adverse events was observed.

Trial registration: ClinicalTrials.gov NCT02970305 NCT04531982.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.

Figures

FIGURE 1
FIGURE 1
Methodology used to conduct the (A) population PK analysis, (B) efficacy E-R analyses, and (C) safety E-R analysis. CCV, coefficient of variation; IIV, intraindividual variability; Ka, Ka absorption rate constant; PK, pharmacokinetic; RV, residual variability; SS, steady state; V/F, apparent volume of distribution.
FIGURE 2
FIGURE 2
Exposure-response model–predicted change from baseline in NSA-16 score according to pimavanserin dose. The model-predicted lines represent the response at the median average daily pimavanserin AUC0–24 at each week for each dose level.
FIGURE 3
FIGURE 3
Exposure-response model–predicted change from baseline in PSP scores according to pimavanserin dose. The model-predicted lines represent the response at the median average daily pimavanserin Cmax at each week for each dose level.
FIGURE 4
FIGURE 4
Exposure-response model–predicted cumulative percent of the negative symptom domain of the CGI-SCH-S.

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Source: PubMed

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