Voriconazole metabolism is influenced by severe inflammation: a prospective study.
During an infection or inflammation, several drug-metabolizing enzymes in the liver are down-regulated, including cytochrome P450 iso-enzymes. Since voriconazole is extensively metabolized by cytochrome P450 iso-enzymes, the metabolism of voriconazole can be influenced during inflammation via reduced clearance of the drug, resulting in higher voriconazole trough concentrations.



To investigate prospectively the influence of inflammation on voriconazole metabolism and voriconazole trough concentrations.



A prospective observational study was performed at the University Medical Center Groningen. Patients were eligible for inclusion if they were ≥18 years old and treated with voriconazole. Voriconazole and voriconazole-N-oxide concentrations were determined in discarded blood samples. To determine the degree of inflammation, C-reactive protein (CRP) concentrations were used. Subsequently, a longitudinal data analysis was performed to assess the effect of inflammation on the metabolic ratio and voriconazole trough concentration.



Thirty-four patients were included. In total 489 voriconazole trough concentrations were included in the longitudinal data analysis. This analysis showed that inflammation, reflected by CRP concentrations, significantly influenced the metabolic ratio, voriconazole trough concentration and voriconazole-N-oxide concentration (all P < 0.001), when corrected for other factors that could influence voriconazole metabolism. The metabolic ratio was decreased by 0.99229Nand the voriconazole-N-oxide concentration by 0.99775N, while the voriconazole trough concentration was increased by 1.005321N, where N is the difference in CRP units (in mg/L).



This study shows that voriconazole metabolism is decreased during inflammation, resulting in higher voriconazole trough concentrations. Therefore, frequent monitoring of voriconazole serum concentrations is recommended during and following severe inflammation.
University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands.
Anette
A
Veringa
University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands.
Mendy
M
Ter Avest
University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, the Netherlands.
Lambert F R
LF
Span
Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, the Netherlands.
Edwin R
ER
van den Heuvel
University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands.
Daan J
DJ
Touw
University Medical Center Groningen, Department of Critical Care, University of Groningen, Groningen, the Netherlands.
Jan G
JG
Zijlstra
University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands.|University of Groningen, Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands.
Jos G W
JG
Kosterink
University Medical Center Groningen, Department of Internal Medicine, University of Groningen, Groningen, the Netherlands.|University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, University of Groningen, Groningen, the Netherlands.
Tjip S
TS
van der Werf
University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands j.w.c.alffenaar@umcg.nl.
Jan-Willem C
JC
Alffenaar
D000046:Academic Medical Centers; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000378:metabolism* / Q000493:pharmacokinetics*; D001711:Biotransformation; D001774:Blood Chemical Analysis; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011446:Prospective Studies; D065819:Voriconazole / Q000378:metabolism* / Q000493:pharmacokinetics*
D000935:Antifungal Agents; D002097:C-Reactive Protein; D065819:Voriconazole