Inflammation altered correlation between CYP2C19 genotype and CYP2C19 activity in patients receiving voriconazole
Clinical and Translational Science, vol. 17, pp. e13887
Abstract
Voriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype-predicted-phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose-corrected voriconazole plasma concentration and C-reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype-predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose-corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose-corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.
Authors 7
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Sylvia D. Klomp Aachen Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
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University Medical Center Groningen · OLVG
Affiliation as printed
Apotheek, OLVG Amsterdam The Netherlands
Department of Clinical Pharmacy and Pharmacology University Medical Center Groningen Groningen The Netherlands
Apotheek, OLVG, Amsterdam, The Netherlands
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
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The University of Sydney · University Medical Center Groningen · Westmead Hospital
Affiliation as printed
Department of Clinical Pharmacy and Pharmacology University Medical Center Groningen Groningen The Netherlands
Faculty of Medicine and Health Sydney School of Pharmacy Sydney New South Wales Australia
The University of Sydney Institute for Infectious Diseases Sydney New South Wales Australia
Westmead Hospital Sydney New South Wales Australia
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
Faculty of Medicine and Health, Sydney School of Pharmacy, Sydney, New South Wales, Australia
The University of Sydney Institute for Infectious Diseases, Sydney, New South Wales, Australia
Westmead Hospital, Sydney, New South Wales, Australia
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Mark G. J. de Boer Aachen Department of Infectious Diseases Leiden University Medical Center Leiden The Netherlands Department of Infectious Diseases
Leiden University Medical Center
Affiliation as printed
Department of Infectious Diseases Leiden University Medical Center Leiden The Netherlands
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
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University Medical Center Groningen
Affiliation as printed
Department of Hematology University Medical Center Groningen Groningen The Netherlands
Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands
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Henk‐Jan Guchelaar Aachen Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
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Jesse Joachim Swen corresponding Aachen Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands
Leiden University Medical Center
Affiliation as printed
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
Department of Clinical Pharmacy & Toxicology Leiden University Medical Center Leiden The Netherlands
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