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, 27 (5), 190-196

Impact of the CYP2C19 Genotype on Voriconazole Exposure in Adults With Invasive Fungal Infections

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Impact of the CYP2C19 Genotype on Voriconazole Exposure in Adults With Invasive Fungal Infections

Issam S Hamadeh et al. Pharmacogenet Genomics.

Abstract

Objectives: Voriconazole, a first-line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant proportion of patients fail to achieve therapeutic trough concentrations with standard weight-based voriconazole dosing, placing them at increased risk for treatment failure, which can be life threatening. We sought to test the association between the CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs.

Patient and methods: Adults receiving weight-based voriconazole dosing for the treatment of IFIs were genotyped for the CYP2C19*2, *3, and *17 polymorphisms, and CYP2C19 metabolizer phenotypes were inferred. Steady-state voriconazole trough plasma concentrations and the prevalence of subtherapeutic troughs (<2 mg/l) were compared between patients with the CYP2C19*17/*17 (ultrarapid metabolizer, UM) or *1/*17 (rapid metabolizer, RM) genotype versus those with other genotypes. Logistic regression, adjusting for clinical factors, was performed to estimate the odds of subtherapeutic concentrations.

Results: Of 70 patients included (mean age 52.5±18 years), 39% were RMs or UMs. Compared with patients with the other phenotypes, RMs/UMs had a lower steady-state trough concentration (4.26±2.2 vs. 2.86±2.3, P=0.0093) and a higher prevalence of subtherapeutic troughs (16 vs. 52%, P=0.0028), with an odds ratio of 5.6 (95% confidence interval: 1.64-19.24, P=0.0044).

Conclusion: Our findings indicate that adults with the CYP2C19 RM or UM phenotype are more likely to have subtherapeutic concentrations with weight-based voriconazole dosing. These results corroborate previous findings in children and support the potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

Conflict of interest statement

Conflicts of Interests/Disclosures: None

Figures

Figure 1
Figure 1
Steady state voriconazole trough plasma concentration in patients with the CYP2C19*17/*17 genotype (ultrarapid metabolizer phenotype, UM), *1/*17 genotype (rapid metabolizer phenotype, RM), and other genotypes (*1/*1, *1/2, *2/2, or *2/*17).
Figure 2
Figure 2
Prevalence of subtherapeutic voriconazole trough plasma concentration at steady state in patients with the CYP2C19*17/*17 genotype (ultrarapid metabolizer phenotype, UM), CYP2C19*1/*17 genotype (rapid metabolizer phenotype, RM) and the other CYP2C19 genotypes (*1/*1, *1/2, *2/2, or 2/*17).
Figure 3
Figure 3
Prevalence of the supratherapeutic voriconazole trough plasma concentration at steady state in CYP2C19 rapid and ultrarapid metabolizers combined (RMs and UMs), normal metabolizers (NMs) and intermediate and poor metabolizers combined (IMs and PMs).

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