Relationship between CYP2D6 Genotype and Haloperidol Pharmacokinetics and Extrapyramidal Symptoms in Healthy Volunteers

Abstract

Aim: This study aimed to elucidate the relationship between CYP2D6 genotype and haloperidol pharmacokinetics and induced extrapyramidal symptoms (EPSs). Materials & methods: Twenty five healthy subjects were included in this randomized, placebo-controlled, single-dose (5 mg) crossover and double-blind clinical trial, selected according to their CYP2D6 genotype and classified as poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7). Results & conclusion: We confirm that CYP2D6 genotype partially determines haloperidol metabolism and the rate of EPSs measured as wakefulness activity by actigraphy. The best predictor of wakefulness activity was the model including haloperidol area under the plasma concentration–time curve, sex and tranquilization, which explained 48.3% of the total variance. However, other markers need to be identified in order to explain the observed variability of haloperidol response and to develop pharmacogenetic predictors of haloperidol-induced EPSs.

KEYWORDS::

• CYP2D6
• extrapyramidal symptoms
• haloperidol
• healthy volunteers
• pharmacogenetics
• randomized clinical trial

Acknowledgements

The authors would like to thank the team of the Drug Research Center, Santa Creu i Sant Pau Hospital, Barcelona, Spain, and the team of the Clinical Trials Unit and the Clinical Pharmacology Service of the Hospital Clinic. The authors thank the Department of Nuclear Medicine, Santa Creu i Sant Pau Hospital, for the SPECT procedures, F Torres for help in the statistical analysis and the Language Advisory Service at the University of Barcelona, Spain, for manuscript revision. The authors also thank M Pares and B Saiani for clinical trial monitoring, and A Meseguer for sample collection assistance.

Financial & competing interests disclosure

This research was funded by the Spanish Ministry of Health (TRA065). Support was also given by the Generalitat de Catalunya to the Schizophrenia Research Group (2009 SGR 1295) and to the Clinical Pharmacology and Pharmacogenetics Group (2009 SGR 1501). P Gassó was funded by the Carlos III Research Institute of the Spanish Ministry of Health (‘Sara Borrell‘ contract [grant CD09/00296]). The funding sources played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was funded by the Spanish Ministry of Health (TRA065). Support was also given by the Generalitat de Catalunya to the Schizophrenia Research Group (2009 SGR 1295) and to the Clinical Pharmacology and Pharmacogenetics Group (2009 SGR 1501). P Gassó was funded by the Carlos III Research Institute of the Spanish Ministry of Health (‘Sara Borrell‘ contract [grant CD09/00296]). The funding sources played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.