Inflammation is the main risk factor of voriconazole overdose in hematological patients

Abstract

Aim: 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.\n\nMethods: 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 [&ge;] 4 mg/l; n = 31) were compared to controls (no VRC overdose: defined by VRC Cmin < 4 mg/L; n = 31) using non-parametric or Chi-square tests followed by multivariable analysis.\n\nResults: VRC overdoses were significantly associated with high CRP and bilirubin levels, intra-venous administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a genetic score1) 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 [&le;] 96 mg/l.\n\nConclusion: 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.