Voriconazole Therapeutic Drug Monitoring: Relationship between Drug Levels and Liver Function Tests.

Abstract

Voriconazole is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. However, the clinical significance of this is unknown. There is some evidence that toxicity rates are higher in patients with higher voriconazole levels (Boyd et al. Clin Infect Dis 2004; 39:1241–1244). In a preliminary study of 41 voriconazole levels in 25 patients, we had found that voriconazole levels correlated with aspartate aminotransferase (AST) and alkaline phosphatase (AP) levels (Trifilio et al. Bone Marrow Transplant 2005; 35:509–513). It was unclear if the abnormal liver function was the cause or the result of higher voriconazole levels. To further elucidate this relationship, we analyzed data on 171 steady-state plasma trough levels performed after at least 5 days of voriconazole therapy in 87 patients with hematologic malignancies. There were 1–5 levels per patient (median 2). Most patients had undergone allogeneic hematopoietic stem cell transplantation. Drug levels were monitored using HPLC (Pennick et al. Antimicrob Agents Chemother 2003; 47:2348–2350). Of the 201 samples assayed, 30 were below the detection limit of the assay (0.2 μg/mL), and were excluded. The daily voriconazole dose (divided into 2) was 200 mg (n=3), 400 mg (n=129), 500 mg (n=18), 600 mg (n=15), or 800 mg (n=6); corresponding to 2.0–13.3 mg/kg (median 5.3). The voriconazole levels were 0.2–12.5 μg/mL (median 1.7). The table shows the correlation between voriconazole levels, and weight, dose and biochemical parameters individually.However, in multivariate regression analysis, the parameters found to correlate significantly with voriconazole levels were ALT (P=0.0005), AST (P=0.003), and AP (P=0.027). The relationship with albumin was of borderline significance (P=0.062). Importantly, the daily dose of voriconazole in mg or in mg/kg was not predictive of drug levels. This larger data set confirms our previous observation that there is a significant relationship between elevated liver function tests and higher voriconazole levels. However, because of the relatively high frequency of abnormal liver function tests in such groups of patients, the cause-effect relationship still remains uncertain. These data suggest that pending further clarification, voriconazole levels may need to be monitored in patients with significantly abnormal liver function tests.ParameterMedian (range)rPDose (mg)400 (200–800)0.190.013Weight (kg)80 (39–135)0.180.018Dose (mg/kg)5.3 (2.0–13.3)0.230.002ALT (IU/L)25 (4–608)0.100.25AST (IU/L)25 (6–524)0.140.11AP (IU/L)95 (27–920)0.270.002Bilirubin (mg/dL)1.1 (0.1–17.3)0.010.89Albumin (g/dL)2.4 (0.8–3.9)0.280.001Creatinine (mg/dL)1.1 (0.2–10.1)0.010.92