Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring

Abstract

Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.

Fig 1

Boxplot of relationship between voriconazole daily dose and voriconazole trough concentration. The box line and corresponding value represent the median voriconazole trough concentration within the dose group; the lower and upper box ends represent the lower and upper quartile, respectively. The lower and upper whiskers represent the minimum and maximum concentrations within 1.5 times the interquartile range (box length) from the lower and upper quartile, respectively. Open circles represent concentrations >1.5 times interquartile range above the upper quartile.

Fig 2

Receiver operating characteristic (ROC) curves for predicting treatment success for all treatment patients (A) and for patients with proven or probable IFI (B) or neurotoxic adverse events (C) from voriconazole trough concentrations. The true-positive rate represents the proportion of true positives that are correctly classified as positive. The false-positive rate represents the proportion of true negatives that are incorrectly classified as positive. True-positive rate = true positives/(true positives + false negatives); false-positive rate = false positives/(false positives + true negatives). 95% CI, 95% confidence interval.