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 reduce...

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Vydáno v:	Journal of antimicrobial chemotherapy Ročník 72; číslo 1; s. 261
Hlavní autoři:	Veringa, Anette, Ter Avest, Mendy, Span, Lambert F R, van den Heuvel, Edwin R, Touw, Daan J, Zijlstra, Jan G, Kosterink, Jos G W, van der Werf, Tjip S, Alffenaar, Jan-Willem C
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England 01.01.2017
Témata:	Academic Medical Centers Adult Aged Antifungal Agents - metabolism Antifungal Agents - pharmacokinetics Biotransformation Blood Chemical Analysis C-Reactive Protein - analysis Female Humans Inflammation - pathology Male Middle Aged Netherlands Prospective Studies Voriconazole - metabolism Voriconazole - pharmacokinetics
ISSN:	1460-2091, 1460-2091
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Abstract	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 0.99229 and the voriconazole-N-oxide concentration by 0.99775 , while the voriconazole trough concentration was increased by 1.005321 , 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.
AbstractList	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.BACKGROUNDDuring 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.OBJECTIVETo 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.METHODSA 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 0.99229N and 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).RESULTSThirty-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 0.99229N and 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.CONCLUSIONSThis 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. 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 0.99229 and the voriconazole-N-oxide concentration by 0.99775 , while the voriconazole trough concentration was increased by 1.005321 , 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.
Author	Alffenaar, Jan-Willem C Zijlstra, Jan G Ter Avest, Mendy Touw, Daan J Span, Lambert F R van den Heuvel, Edwin R Veringa, Anette Kosterink, Jos G W van der Werf, Tjip S
Author_xml	– sequence: 1 givenname: Anette surname: Veringa fullname: Veringa, Anette organization: University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands – sequence: 2 givenname: Mendy surname: Ter Avest fullname: Ter Avest, Mendy organization: University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands – sequence: 3 givenname: Lambert F R surname: Span fullname: Span, Lambert F R organization: University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, the Netherlands – sequence: 4 givenname: Edwin R surname: van den Heuvel fullname: van den Heuvel, Edwin R organization: Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, the Netherlands – sequence: 5 givenname: Daan J surname: Touw fullname: Touw, Daan J organization: University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands – sequence: 6 givenname: Jan G surname: Zijlstra fullname: Zijlstra, Jan G organization: University Medical Center Groningen, Department of Critical Care, University of Groningen, Groningen, the Netherlands – sequence: 7 givenname: Jos G W surname: Kosterink fullname: Kosterink, Jos G W organization: University of Groningen, Department of Pharmacy, Section of Pharmacotherapy and Pharmaceutical Care, Groningen, the Netherlands – sequence: 8 givenname: Tjip S surname: van der Werf fullname: van der Werf, Tjip S organization: University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, University of Groningen, Groningen, the Netherlands – sequence: 9 givenname: Jan-Willem C surname: Alffenaar fullname: Alffenaar, Jan-Willem C email: j.w.c.alffenaar@umcg.nl organization: University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, University of Groningen, Groningen, the Netherlands j.w.c.alffenaar@umcg.nl
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Copyright	The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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SubjectTerms	Academic Medical Centers Adult Aged Antifungal Agents - metabolism Antifungal Agents - pharmacokinetics Biotransformation Blood Chemical Analysis C-Reactive Protein - analysis Female Humans Inflammation - pathology Male Middle Aged Netherlands Prospective Studies Voriconazole - metabolism Voriconazole - pharmacokinetics
Title	Voriconazole metabolism is influenced by severe inflammation: a prospective study
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