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Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics

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Abstract

Background and Objectives

Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors.

Methods

Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography–ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism.

Results

A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis.

Conclusions

This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials.

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Acknowledgments

This work has been supported by the Bridging Grant from Universiti Sains Malaysia (grant no. 304.PFARMASI.6316196). The authors acknowledge the USM Pusat Sejahtera staff for assisting in the clinical study and data collection.

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  1. Orwa Albitar

    Present address: Roche Pharma Research and Early Development, Basel, Switzerland

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Universiti Sains Malaysia, USM, 11800, Gelugor, Penang, Malaysia

    Orwa Albitar, Sabariah Noor Harun & Siti Maisharah Sheikh Ghadzi

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Correspondence to Siti Maisharah Sheikh Ghadzi.

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Funding

This work was supported by the Bridging Grant, Universiti Sains Malaysia (Grant no. 304.PFARMASI.6316196).

Conflict of Interest:

The authors declare that they have no conflict of interest.

Ethics Approval

This study was approved by the Human Research Ethics Committee USM, Division of Research and Innovation (R&I), USM Health Campus, Malaysia (USM/JEPeM/20090488).

Consent to Participate

All participants provided written informed consent before enrollment into the study.

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Not applicable.

Availability of Data and Material:

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability:

The model structure and parameters were estimated using NONMEM 7.4.2 and the model code is provided in the supplementary.

Author Contributions

All authors have read and approved the final submitted manuscript, and agree to be accountable for the work. O.A. and S.M.S.G. designed the study. O.A. collected and analysed the data and drafted the manuscript. S.M.S.G. and S.N.H. supported the data analysis and finalised the manuscript.

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Albitar, O., Harun, S.N. & Sheikh Ghadzi, S.M. Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics. CNS Drugs 38, 571–581 (2024). https://doi.org/10.1007/s40263-024-01092-1

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