Voriconazole therapeutic drug monitoring: Factors associated with supratherapeutic and subtherapeutic voriconazole concentrations

Objective: The voriconazole trough concentration (C_min) varies widely, and C_min outside the therapeutic range (COTR) is associated with response failure and toxicity. The objective of this study was to identify potential factors associated with COTR in patients, and specifically the population at a high risk of COTR. Materials and methods: We performed a retrospective study of patients who received voriconazole from 2009 to 2016. Voriconazole C_min values were analyzed with high-performance liquid chromatography, and values of < 1 mg/L and > 4 mg/L were defined as COTR. Logistic regression and the classification and regression tree (CART) were used to explore the potential factors associated with COTR. Results: In total, 134 voriconazole C_min values were measured in 64 patients who met the eligibility criteria: 55 (41.0%) were subtherapeutic, and 79 (59.0%) were supratherapeutic. Logistic regression revealed that voriconazole COTR was significantly associated with age, CYP2C19 genetic status, and liver function after voriconazole treatment. CART identifed the high-risk population of COTR: (1) patients' age < 47 years and with underlying liver disease, (2) patients' age > 47 years and with acute liver dysfunction after voriconazole treatment, (3) non-poor metabolizers, aged from 46 to 65 years and with normal liver function after voriconazole treatment, and (4) old (age > 65 years) patients with normal liver function and body weight < 66 kg. Conclusion: Our findings suggest that age, CYP2C19 genetic status, and liver function status are strongest predictors of voriconazole COTR. Clinically, these results can be used to estimate the probability of voriconazole COTR in individual patients.