Voriconazole Pharmacokinetics Following HSCT: Results from the BMT CTN 0101 Trial

Publication Type
Journal Article
Year of Publication
2016
Authors
Hope, William W; Walsh, Thomas J; Goodwin, Joanne; Peloquin, Charles A; Howard, Alan; Kurtzberg, Joanne; Mendizabal, Alan; Confer, Dennis L; Bulitta, J├╝rgen; Baden, Lindsey R; Neely, Michael N; Wingard, John R; The Blood and Marrow Transplant Clinical Trials Network
Secondary
J Antimicrob Chemother
Volume
71
Start Page
2234
Pagination
2234-2240
Date Published
08/2016
Keywords
Adolescent; Adult; Aged; Antifungal Agents; Area Under Curve; Double-Blind Method; Female; Humans; Male; Middle Aged; Plasma; Prospective Studies; Voriconazole; Young Adult
Abstract

BACKGROUND: Voriconazole is a first-line agent for the prevention and treatment of a number of invasive fungal diseases. Relatively little is known about the relationship between drug exposure and the prevention of invasive fungal infections.

PATIENTS AND METHODS: A pharmacokinetic-pharmacodynamic substudy was performed as part of the BMT CTN 0101 trial, which was a randomized clinical trial comparing voriconazole with fluconazole for the prevention of invasive fungal infections in HSCT recipients. A previously described population pharmacokinetic model was used to calculate the maximum a posteriori Bayesian estimates for 187 patients. Drug exposure in each patient was quantified in terms of the average AUC and average trough concentrations. The relationship between drug exposure and the probability of breakthrough infection was investigated using logistic regression. AUC and trough concentrations in patients with and without breakthrough infection were compared.

RESULTS: Pharmacokinetic data from each patient were readily described using the maximum a posteriori Bayesian estimates. There were only five patients that had a breakthrough infection while receiving voriconazole in the first 100 days post-HSCT. For these patients, there was no statistically significant relationship between the average AUC or average trough concentration and the probability of breakthrough infection [OR (95% CI) 1.026 (0.956-1.102) and 1.108 (0.475-2.581), respectively]. P value for these estimates was 0.474 and 0.813, respectively.

CONCLUSIONS: Given the very small number of proven/probable infections, it was difficult to identify any differences in drug exposure in HSCT recipients with and without breakthrough fungal infections.