Effect of CYP2D6 on Risperidone Pharmacokinetics and Extrapyramidal Symptoms in Healthy Volunteers: Results from a Pharmacogenetic Clinical Trial

Abstract

Aim: To elucidate the relationship between CYP2D6 genotype and risperidone pharmacokinetics and extrapyramidal symptoms we propose the APSEP pharmacogenetic clinical trial. Materials & methods: Twenty-five healthy subjects were included in this randomized, placebo-controlled, single dose (risperidone 2.5 mg) crossover and double-blind clinical trial. Subjects were selected according to their CYP2D6 genotype and classified as: poor metabolizers (n = 8), extensive metabolizers (n = 10) and ultrarapid metabolizers (n = 7). Results & conclusion: Our study demonstrates that CYP2D6 predicted 65% of the risperidone metabolism variability. Moreover, its ability to predict actigraphy records is similar to the predictive power of pharmacokinetic parameters (24%). Our results also highlight the need for the development of pharmacogenetic predictors that take into account the complexity of pharmacokinetic and pharmacodynamic relationships.

KEYWORDS::

• CYP2D6
• extrapyramidal symptoms
• pharmacogenetics
• randomized clinical trial
• risperidone

Acknowledgements

The authors thank the team of the Drug Research Centre, 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 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.