Mediation and longitudinal analysis to interpret the association between clozapine pharmacokinetics, pharmacogenomics, and absolute neutrophil count

Lock, Siobhan K., Legge, Sophie E., Kappel, Djenifer B., Willcocks, Isabella R. ORCID: https://orcid.org/0000-0002-3568-5236, Helthius, Marinka, Jansen, John, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379 and Pardiñas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590 2023. Mediation and longitudinal analysis to interpret the association between clozapine pharmacokinetics, pharmacogenomics, and absolute neutrophil count. Schizophrenia 9 , 74. 10.1038/s41537-023-00404-6

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Abstract

Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently experiencing neutropenia (N = 811). Increased daily clozapine dose was associated with elevated neutrophil count, amounting to a 133 cells/mm3 rise per standard deviation increase in clozapine dose. One-third of the total effect of clozapine dose was mediated by plasma clozapine and norclozapine levels, which themselves demonstrated opposing, independent associations with absolute neutrophil count. Finally, CYP1A2 pharmacogenomic activity score was associated with absolute neutrophil count, supporting lower neutrophil levels in CYP1A2 poor metabolisers during clozapine use. This information may facilitate identifying at-risk patients and then introducing preventative interventions or individualised pharmacovigilance procedures to help mitigate these adverse haematological reactions.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Nature Publishing Group UK
Funders:	MRC
Date of First Compliant Deposit:	11 October 2023
Date of Acceptance:	10 October 2023
Last Modified:	31 Oct 2023 14:47
URI:	https://orca.cardiff.ac.uk/id/eprint/163127

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