Voriconazole pharmacokinetics following HSCT: results from the BMT CTN 0101 trial.
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.



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.



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.



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.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK william.hope@liverpool.ac.uk.
William W
WW
Hope
Transplantation-Oncology Infectious Diseases Program, Departments of Medicine, Pediatrics, and Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, NY, USA.
Thomas J
TJ
Walsh
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Joanne
J
Goodwin
University of Florida, Gainesville, FL, USA.
Charles A
CA
Peloquin
Center for International Blood and Marrow Transplant Research, Minneapolis, MN, USA.
Alan
A
Howard
Duke University, Durham, NC, USA.
Joanne
J
Kurtzberg
Emmes Corp., Rockville, MD, USA.
Alan
A
Mendizabal
National Marrow Donor Program, Minneapolis, MN, USA.
Dennis L
DL
Confer
Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA.
Jürgen
J
Bulitta
Dana-Farber Cancer Institute, Boston, MA, USA.
Lindsey R
LR
Baden
University of Southern California, Los Angeles, CA, USA.
Michael N
MN
Neely
University of Florida, Gainesville, FL, USA.
John R
JR
Wingard
D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D065819:Voriconazole / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
D000935:Antifungal Agents; D065819:Voriconazole