Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy

ABSTRACT

Introduction: Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class.

Areas covered: This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability. A search of English language original research, and scholarly reviews describing the pharmacogenomics of triazole antifungal agents and their impact on drug efficacy, safety, and tolerability published from 1980 to present was undertaken using PubMed.

Expert opinion: Currently studies demonstrating the pharmacogenomic influences on itraconazole, posaconazole and isavuconazole are minimal and limited to their inhibitory effects on CYP3A4 in expressors of CYP3A5 variants. Conversely, there are significant pharmacogenomic considerations for voriconazole because it interacts with several polymorphic CYPs, most notably CYP2C19. Pharmacogenomics of CYP2C9 do not appear to effect fluconazole safety and efficacy. However, genetic polymorphisms may influence its drug interactions but this needs further study.

KEYWORDS:

• CYP2C19
• CYP2C9
• CYP3A4
• CYP3A5
• Cytochrome P450
• fluconazole
• isavuconazole
• pharmacogenetics
• pharmacogenomics
• voriconazole

Article highlights

• Itraconazole, Posaconazole, Isavuconazole are minimally effected by pharmacogenomics polymorphisms of CYP3A4/5

• Fluconazole efficacy and safety is not effected by pharmacogenomics polymorphisms of CYP2C9

• Fluconazole drug interactions in the presence of genetic polymorphisms of CYP2C9 and/or CYP2C19 need further study

• Voriconazole efficacy and safety is indirectly effected by the CYP2C19, but not CYP3A4 and CYP2C9

• Genetic polymorphisms of CYP2C19 do impact voriconazole systemic concentrations, which are implicated in both its safety and efficacy

• Voriconazole therapeutic drug monitoring is recommended, but genotype-derived dosing cannot be recommended at this time

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.