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

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 How to cite this article: Mostafa S, Polasek TM, Bousman C, et al. Delineating gene-environment effects using virtual twins of patients treated with clozapine. CPT

Seeing what is behind the smokescreen: A systematic review of methodological aspects of smoking interaction studies over the last three decades and implications for future clinical trials

“…Considering these gene‐smoking interactions of CYP1A2 are important, as individuals with low‐inducible genotypes will have hardly any increased level of CYP1A2 activity as a result of smoking. The impact of accounting for such interaction terms of covariates has been confirmed recently 50 …”

“…The impact of accounting for such interaction terms of covariates has been confirmed recently. 50 In conclusion, the systematic review of the most recent smoking interaction studies in healthy subjects provides valuable insights on how regulatory smoking DDI evaluations can be improved to inform adequate dosing recommendations in smokers.…”

Virtual twins for model‐informed precision dosing of clozapine in patients with treatment‐resistant schizophrenia

“…These results confirm our previous work demonstrating that MIPD-VT can reasonably predict clozapine steady-state concentrations in real patients (R 2 = 0.29 compared with R 2 = 0.37 previously). 11 A particular strength of the study was that all individual simulations were undertaken without knowledge of the final clinical outcome and concentration (blinded).…”

“…Individual VTs were constructed in Simcyp version 21, as previously described by Mostafa et al 11 In short, each participant was matched for demographics, clozapine dose, CYP phenotypes, and the presence of inhibitors and inducers (see Table 1). Fluvoxamine and bupropion were the only inhibitors with validated inhibitor drug profiles in Simcyp and were accounted for when co-prescribed with clozapine.…”

“…In our previous study, 11 we built VTs of 42 clozapine‐treated patients using Simcyp and evaluated the impact of systematically increasing the virtualization of covariates on predicted clozapine PKs. Three evaluation scenarios were simulated: low (demographic), medium (demographic and environmental), and high (demographic, environmental, and genetic) covariate virtualization.…”