Abstract
Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited.
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Acknowledgements
The authors wish to acknowledge the Cooperative Research Centre (CRC) Scientific Advisory Committee, in addition to the contributions of study participants, clinicians at recruitment services, staff at the Murdoch Children’s Research Institute, staff at the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging, and research staff at the Melbourne Neuropsychiatry Centre, including coordinators Phassouliotis, C., Merritt, A., and research assistants, Burnside, A., Cross, H., Gale, S., and Tahtalian, S. Participants for this study were sourced, in part, through the Australian Schizophrenia Research Bank (ASRB), which is supported by the National Health and Medical Research Council of Australia (Enabling Grant N. 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. The authors acknowledge the financial support of The CRC programme, an Australian Government Initiative. DL was supported by the J.N. Peters Postdoctoral Fellowship awarded by the University of Melbourne. CP was supported by an NHMRC Senior Principal Research Fellowship (1105825), and a Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Award. CAB was supported by an NHMRC Career Development Fellowship (1127700), The University of Calgary Cumming School of Medicine, and the Alberta Children’s Hospital Foundation. None of the funding sources played any role in the study design; collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
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SM is an employee of myDNA Inc., a company that provides pharmacogenetic testing. CP has participated on Advisory Boards for Janssen-Cilag, Astra-Zeneca, Lundbeck, and Servier. He has received honoraria for talks presented at educational meetings organized by Astra-Zeneca, Janssen-Cilag, Eli-Lilly, Pfizer, Lundbeck, and Shire. CAB is a member of Clinical Pharmacogenetics Implementation Consortium and the Genetic Testing Committee of the International Society of Psychiatric Genetics. He has also received material support from Assurex, CNSDose, Genomind, and AB-Biotics for research purposes and has ongoing research collaborations with MyDNA but does not have equity, stocks, or options in these companies or any other pharmacogenetic companies. The other authors of this manuscript have no relevant disclosures.
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Lesche, D., Mostafa, S., Everall, I. et al. Impact of CYP1A2, CYP2C19, and CYP2D6 genotype- and phenoconversion-predicted enzyme activity on clozapine exposure and symptom severity. Pharmacogenomics J 20, 192–201 (2020). https://doi.org/10.1038/s41397-019-0108-y
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DOI: https://doi.org/10.1038/s41397-019-0108-y