Azole antifungals and inter-individual differences in drug metabolism: the role of pharmacogenomics and precision medicine

ABSTRACT

Introduction

Azole antifungal drugs are commonly prescribed to treat invasive fungal infections in various disease conditions. However, these drugs are substrates and inhibitors of cytochrome P450 (CYP) enzymes, UGT1A4, and P-gp. The genetic variants of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4 can modify the safety or effectiveness of azole antifungals.

Areas covered

This review has collated the recent advances in the pharmacogenomics of azole antifungals pertaining to their metabolism and the safety or effectiveness of their use. A literature search was performed in PubMed from inception to the 5^th of December 2022 to retrieve articles focusing on pharmacogenomics of azole antifungals.

Expert opinion

Optimizing the safety or effectiveness of most azole antifungals, excluding voriconazole, through pharmacogenomics remains largely theoretical, pending laboratory assessment in future studies. However, the ample evidence of the clinically significant pharmacogenetic impacts of voriconazole, due to the CYP2C19 genetic variability, favors clinical implementation. The inconsistencies of the pharmacogenomics-based dosing guidelines for voriconazole, from different international pharmacogenomics working groups, may hinder clinicians in assimilating and applying such pharmacogenetic information into clinical practice. Consideration of drug–drug interactions along with the pharmacogenetic effects may advance the precision medicine of azole antifungals and allow greater effectiveness in clinical practice.

KEYWORDS:

• Azole antifungals
• genetic polymorphisms
• safety and effectiveness
• dosing guidelines
• precision medicine

Article highlights

• The safety and effectiveness of voriconazole is affected by the CYP2C19 genetic variants.

• The trough concentration of voriconazole may significantly increase (~2–5-fold) in intermediate and poor metabolizers due to the CYP2C19 genetic variability.

• The higher blood concentration of voriconazole accounts for the treatment success rate but may lead to drug toxicity, e.g. hepatotoxicity.

• CYP2C19 genotype guided therapy of voriconazole is recommended by the CPIC and DPWG.

• Multifactorial DGIs of voriconazole may occur and should examine such combined effects in future studies for patients taking voriconazole.

• The efficacy of fluconazole, ketoconazole, itraconazole, posaconazole, and isavuconazole may be affected by the genetic polymorphisms of CYP3A4/5, CYP2C9, CYP2C19, ABCB1, or UGT1A4, but the current evidence for these associations is insufficient.

• Extensive pharmacogenomic research may increase the availability of robust evidence for strengthening the precision medicine of azole antifungal drugs.

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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.