Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections

Abstract

Objective Voriconazole, a first line agent for the treatment of invasive fungal infections (IFIs), is metabolized by CYP2C19. A significant portion 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 CYP2C19 genotype and subtherapeutic voriconazole concentrations in adults with IFIs. 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 metabolizers, UMs) or *1/*17 genotypes (rapid metabolizers, RMs) 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 51±18 years), 39% were RMs or UMs. Compared to 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=0.0059). 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 potential clinical utility of CYP2C19 genotype-guided voriconazole dosing to avoid underexposure in RMs and UMs.

Prospective CYP2C19‐Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations

“…Although therapeutic drug monitoring was not performed for every CYP2C19 genotyped patient prescribed voriconazole, the majority of CYP2C19 rapid metabolizers (41 of 58; 70.7%) did have trough concentrations collected, which was the primary focus for this investigation. By study design, a limited number of CYP2C19 rapid metabolizers received the standard voriconazole prophylactic dosage of 200 mg twice daily, but observed trough concentrations were consistent with prior published studies . Greater therapeutic drug monitoring among other CYP2C19 diplotypes may have further elucidated the application of CYP2C19 ‐guided voriconazole dosing.…”

“…By study design, a limited number of CYP2C19 rapid metabolizers received the standard voriconazole prophylactic dosage of 200 mg twice daily, but observed trough concentrations were consistent with prior published studies. 15,20 Greater therapeutic drug monitoring among other CYP2C19 diplotypes may have further elucidated the application of CYP2C19-guided voriconazole dosing.…”

“…Among the stratified groups, CYP2C19 rapid metabolizers (CYP2C19*1/*17) receiving the standard prophylactic voriconazole dosage had significantly lower trough concentrations (median 0.6 μg/mL; P = 0.03; Figure 1a and Figure S6), which is consistent with historical data. [12][13][14][15][17][18][19][20] CYP2C19 rapid metabolizers receiving interventional voriconazole 300 mg twice daily attained higher trough concentrations (median 2.7 μg/ mL) when compared with those receiving 200 mg twice daily (P = 0.001; Figure 1a and Figure S6).…”

Value of Supportive Care Pharmacogenomics in Oncology Practice

“…Importantly, CYP2C19 is responsible for the majority of voriconazole metabolism; thus, polymorphisms in this gene can have a significant effect on serum concentrations . The patients at greatest risk of inadequate drug concentrations and thus voriconazole failure are those with rapid CYP2C19 metabolism, which occurs in up to 30%–35% of whites and blacks, such that the drug is removed from the bloodstream too quickly and can never reach therapeutic levels . Preliminary data show that, in a population of stem cell transplant patients, genotype‐guided dosing for voriconazole prophylaxis (higher initial doses for CYP2C19 rapid and ultrarapid metabolizers) resulted in zero cases of subtherapeutic initial trough concentrations in this subset of patients compared with 80% in historical controls ( p < .001) .…”

Evaluation of CYP2C19 Genotype‐Guided Voriconazole Prophylaxis After Allogeneic Hematopoietic Cell Transplant

“…There were only three UMs and four PMs in this study, all of whom achieved therapeutic concentrations; thus, this requires validation in larger cohorts of patients. Although our study was conducted in patients requiring prophylaxis, the same concept can be applied to those receiving treatment doses by initiating 5 mg/kg maintenance dose in RMs/UMs compared with 4 mg/kg in all other patients, as suggested by Hamadeh et al …”