Exploring clozapine pharmacokinetics in Tunisian schizophrenic patients: A population-based modelling approach investigating the impact of genetic and non-genetic variables.

Publisher: Blackwell Country of Publication: England NLM ID: 101208422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-7843 (Electronic) Linking ISSN: 17427835 NLM ISO Abbreviation: Basic Clin Pharmacol Toxicol Subsets: MEDLINE

Publication: <2005-> : Oxford : Blackwell
Original Publication: Copenhagen, Denmark : Oxford, UK : Nordic Pharmacological Society Distributed by Blackwell Munksgaard, 2004-

Clozapine*/pharmacokinetics ; Clozapine*/blood ; Schizophrenia*/drug therapy ; Schizophrenia*/genetics ; Cytochrome P-450 CYP1A2*/genetics ; Cytochrome P-450 CYP1A2*/metabolism ; Antipsychotic Agents*/pharmacokinetics ; Cytochrome P-450 CYP2C19*/genetics; Humans ; Male ; Female ; Tunisia ; Adult ; Cross-Sectional Studies ; Middle Aged ; Models, Biological ; Smoking ; Young Adult ; Polymorphism, Genetic

Clozapine is characterized by a large within- and between-patient variability in its pharmacokinetics, attributed to non-genetic and genetic factors. A cross-sectional analysis of clozapine trough concentration (Clz C0) issued from Tunisian schizophrenic patients was collected and analysed using a nonparametric modelling approach. We assessed the impact of demographic covariates (age, weight and sex), patient's habits (smoking status, alcohol and caffeine intake) and the genetic factors (CYP1A2*1C, CYP1A2*1F and CYP2C19*2 polymorphisms) on each pharmacokinetic parameter. An external validation of this pharmacokinetic model using an independent data set was performed. Fit goodness between observed- and individual-predicted data was evaluated using the mean prediction error (% MPE), the mean absolute prediction error (% MAPE) as a measure of bias, and the root mean squared error (% RMSE) as a measure of precision. Sixty-three CLz C0 values issued from 51 schizophrenic patients were assessed in this study and divided into building and validation groups. CYP1A2*1F polymorphism and smoking status were the only covariates significantly associated with clozapine clearance. Precision parameters were as follows: 1.02%, 0.95% and 22.4%, respectively, for % MPE, % MAPE and % RMSE. We developed and validated an accurate pharmacokinetic model able to predict Clz C0 in Tunisian schizophrenic patients using the two parameters CYP1A2*1F polymorphism and smoking.
(© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

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Keywords: clozapine; population pharmacokinetic; schizophrenia; therapeutic drug monitoring; trough concentration

0 (CYP1A2 protein, human)
0 (CYP2C19 protein, human)

Date Created: 20240410 Date Completed: 20240517 Latest Revision: 20240517

20240517

10.1111/bcpt.14009

38599832