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Delineating gene–environment effects using virtual twins of patients treated with clozapine

Delineating gene–environment effects using virtual twins of patients treated with clozapine

Authors :
Sam Mostafa
Thomas M. Polasek
Chad Bousman
Amin Rostami‐Hodjegan
Leslie J. Sheffield
Ian Everall
Christos Pantelis
Carl M. J. Kirkpatrick
Source :
CPT: Pharmacometrics & Systems Pharmacology, Vol 12, Iss 2, Pp 168-179 (2023)
Publication Year :
2023
Publisher :
Wiley, 2023.

Abstract

Abstract Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model‐informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine‐treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: “low” (demographic), “medium” (demographic and environmental interaction), and “high” (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R2) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from −138.48 ng/ml to −74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.

Subjects

Subjects :
Therapeutics. Pharmacology
RM1-950

Details

Language :
English
ISSN :
21638306
Volume :
12
Issue :
2
Database :
Directory of Open Access Journals
Journal :
CPT: Pharmacometrics & Systems Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.730d77bd6c7e4a90974bd9c7af6e6367
Document Type :
article
Full Text :
https://doi.org/10.1002/psp4.12886