The Roles of CYP2C19 and CYP3A4 in Voriconazole Pharmacogenetics

Voriconazole is a triazole antifungal agent used to treat serious fungal infections. It is primarily used in immunocompromised patients, such as those undergoing organ transplantation. CYP2C19 is the primary enzyme responsible for voriconazole metabolism. CYP3A4, CYP3A5 and CYP2C9 also play a role, secondary to CYP2C19. The influence of genetic polymorphisms in CYP2C19 is well documented in clinical studies, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) recently released guideline for voriconazole dosing based on CYP2C19 genotype.
In the August issue of Clinical Pharmacology and Therapeutics, Gautier-Veyret et al wrote a perspective piece discussing two retrospective studies showing that genetic variations in CYP3A4 gene may influence voriconazole trough concentrations, suggesting that in addition to CYP2C19, CYP3A4 should also be genotyped for voriconazole dosing.
In response to this, CPIC guideline authors Walsh et al acknowledged the different opinions on the role of CYP3A4 in voriconazole pharmacokinetics and clarified the reasons why CPIC authors feel there is NOT sufficient evidence to recommend altered voriconazole dosing based on genetic polymorphisms in CYP3A4/CYP3A5.
For further details see both articles in the August edition of Clinical Pharmacology and Therapeutics:
1, Response to "Pharmacogenetics of Voriconazole: CYP2C19 but Also CYP3A4 Need to Be Genotyped" - The Role of CYP3A4 and CYP3A5 Polymorphisms in Clinical Pharmacokinetics of Voriconazole.Walsh TJ, Moriyama B, Penzak SR, Klein TE, Caudle KE.Clin Pharmacol Ther. 2017 Aug;102(2):190. doi: 10.1002/cpt.681. Epub 2017 Apr 29. PMID: 28455946
2, Pharmacogenetics of Voriconazole: CYP2C19 but Also CYP3A4 Need to Be Genotyped.Gautier-Veyret E, Fonrose X, Stanke-Labesque F.Clin Pharmacol Ther. 2017 Aug;102(2):189. doi: 10.1002/cpt.662. Epub 2017 May 26. PMID: 28182291
3, CPIC guideline for voriconazole and CYP2C194, Voriconazole pathway on PharmGKB