Inflammation is a potential risk factor of voriconazole overdose in hematological patients.
Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. This case-control study performed in hematological patients who benefited from VRC therapeutic drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC overdose. Pharmacogenetic, biological, and demographic parameters at the time of VRC trough concentration (Cmin ) were retrospectively collected from medical records. Cases (VRC overdose: defined by a VRC Cmin ≥ 4 mg/L; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using nonparametric or chi-square tests followed by multivariable analysis. VRC overdoses were significantly associated with high CRP and bilirubin levels, intravenous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a combined genetic score) were not significantly different between patients who experienced a VRC overdose and those who did not. In multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/L) was the sole independent risk factor of VRC overdose (P < 0.01). Patients with CRP levels > 96 mg/L) had a 27-fold (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/L. This study demonstrates that inflammatory status, assessed by CRP levels, is the main risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic determinants do not appear to be involved.
['Gautier-Veyret|Elodie|E|http://orcid.org/0000-0002-5846-3847', 'Truffot|Aurélie|A|', 'Bailly|Sébastien|S|', 'Fonrose|Xavier|X|', 'Thiebaut-Bertrand|Anne|A|', 'Tonini|Julia|J|', 'Cahn|Jean-Yves|JY|', 'Stanke-Labesque|Françoise|F|']
D000328:Adult D000368:Aged D000935:Antifungal Agents D001663:Bilirubin D015415:Biomarkers D002097:C-Reactive Protein D016903:Drug Monitoring D062787:Drug Overdose D005260:Female D005602:France D019337:Hematologic Neoplasms D006801:Humans D016867:Immunocompromised Host D007249:Inflammation D008297:Male D008875:Middle Aged D009181:Mycoses D012189:Retrospective Studies D012307:Risk Factors D065819:Voriconazole
inflammation voriconazole therapeutic drug monitoring pharmacogenetics