Genotype-Guided Voriconazole Prescribing in Lung Transplant Recipients

Abstract

<h3>Purpose</h3> Voriconazole (VRC) is the treatment of choice for Aspergillus in lung transplant recipients. VRC undergoes metabolism via CYP2C19, a polymorphic enzyme that has varying metabolic activity. Patients with either CYP2C19 ultrarapid metabolizer (URM) or rapid metabolizer (RM) phenotypes are less likely to achieve therapeutic VRC levels, which is predictive of treatment failure. Determining CYP2C19 variations can help tailor VRC therapy for lung transplant recipients. <h3>Methods</h3> This prospective cohort study included lung transplant recipients who received VRC between January 1, 2016, to November 30, 2019. Participants were excluded if they did not read or speak English, did not have access to email or internet, and did not provide consent to pharmacogenomic testing. The frequency of various CYP2C19 genotypes in this cohort was identified. <h3>Results</h3> Forty-three VRC exposures occurred in 34 participants who completed pharmacogenomic testing. Twenty-one percent (7/34) had URM or RM phenotypes, 74% (25/34) had normal (NM) or intermediate (IM) metabolizer phenotypes, and 6% (2/34) had poor metabolizer (PM) phenotype. Participants with URM or RM phenotypes required an average of 40 days to reach first therapeutic VRC levels, compared to 13 days and 9 days in the NM or IM and PM phenotypes, respectively. Eight cystic fibrosis participants were included in this cohort. Cystic fibrosis participants with URM or RM phenotypes required 77 days to reach first therapeutic VRC levels, while NM or IM and PM phenotypes required 27 days and 14 days, respectively. <h3>Conclusion</h3> The time required to achieve therapeutic VRC levels was widely variable based on CYP2C19 genotype and the corresponding phenotype in our study cohort. Participants with URM or RM phenotypes are at high risk for treatment failure due to prolonged time to therapeutic VRC levels. CYP2C19 polymorphism may further reduce likelihood of achieving target VRC levels in cystic fibrosis patients.