Pharmacokinetics and pharmacogenomics of clozapine in an ancestrally diverse sample: A longitudinal analysis and GWAS using clinical monitoring data from the UK

Abstract

Background The antipsychotic clozapine is the only drug with proven effectiveness against the treatment-resistant symptoms that affect 20-30% of those with schizophrenia. Despite this, clozapine is markedly under-prescribed, partly due to concerns about its narrow therapeutic range and adverse drug reaction profile. Both concerns are linked to drug metabolism, which varies across worldwide populations and is partially genetically determined. There is, however, a lack of clozapine pharmacogenomic data based on study participants of multiple ancestries. Methods We analysed data from 4,495 individuals linked to 16,068 assays from a clozapine monitoring service in the UK. Genomic information was used to identify five biogeographical ancestries (European, Sub-Saharan African, North African, Southwest Asian and East Asian) as well as admixed individuals. Pharmacokinetic modelling, GWAS, and a polygenic score association analysis were conducted on this longitudinal dataset using three outcome variables: two metabolite plasma concentrations (clozapine and norclozapine) and their ratio. Findings A faster average clozapine metabolism was seen in those of Sub-Saharan African ancestry compared to Europeans. In contrast, East and Southwest Asians were more likely to be slow clozapine metabolisers. Eight pharmacogenomic loci were identified in the GWAS, with consistent cross-ancestral effects. Polygenic scores generated from these loci led to significant associations with clozapine outcome variables in the whole sample and within individual ancestries, with variances explained between 0.61%-7.26%. Interpretation Longitudinal cross-ancestry GWAS can discover pharmacogenomic markers of clozapine metabolism that, individually or as polygenic scores, have consistent effects across ancestries. While the potential clinical role of these predictors is evaluated, we provide strong evidence that ancestral differences in clozapine metabolism should be incorporated into clozapine dosing and managing protocols to optimise their utility for diverse populations. Funding Medical Research Council (MRC).

Competing Interest Statement

Adrian King is a full-time employee of Magna Laboratories Ltd. Marinka Helthuis and John Jansen are full-time employees of Leyden Delta B.V. Michael J Owen, Michael C O'Donovan and James TR Walters are supported by a collaborative research grant from Takeda Pharmaceuticals Ltd. for a project unrelated to the work presented here.

Funding Statement

Antonio F Pardinas and Djenifer B Kappel were supported by an Academy of Medical Sciences Springboard award (SBF005\1083). The CLOZUK project was supported by the following grants from the Medical Research Council to Cardiff University: Centre (MR/L010305/1), Program (MR/P005748/1), and Project (MR/L011794/1, MC_PC_17212); as well as the European Union (EU) Seventh Framework program (279227, CRESTAR). This work acknowledges the support of the Supercomputing Wales project, which is partly funded by the European Regional Development Fund (ERDF) via Welsh Government.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The CLOZUK project that encompasses this study received UK National Research Ethics Service approval (ref. 10/WSE02/15), following the UK Human Tissue Act.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

To comply with the ethical and regulatory framework of the CLOZUK project, access to individual-level data requires a collaboration agreement with Cardiff University. Requests to access these datasets should be directed to Prof. James T. R. Walters (WaltersJT@cardiff.ac.uk).

留言 (0)

沒有登入
gif