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

Abstract

22Aim: Voriconazole (VRC) overdoses are frequent and expose patients at high risk of adverse effects. 23This case-control study performed in hematological patients who benefited from VRC therapeutic 24 drug monitoring from January 2012 to December 2015 aimed to identify risk factors of VRC 25 overdose. 26Methods: Pharmacogenetic, biological, and demographic parameters at the time of VRC trough 27 concentration (Cmin) were retrospectively collected from medical records. Cases (VRC overdose: 28 defined by a VRC Cmin ≥ 4 mg/l; n = 31) were compared to controls (no VRC overdose: defined by 29 VRC Cmin < 4 mg/L; n = 31) using non-parametric or Chi-square tests followed by multivariable 30 analysis. 31Results: VRC overdoses were significantly associated with high CRP and bilirubin levels, intra-venous 32 administration, and age in univariable analysis. In contrast, the proportion of CYP genotypes 33 (CYP2C19, CYP3A4, or CYP3A5, considered alone or combined in a genetic score 1 ) were not 34 significantly different between patients who experienced a VRC overdose and those who did not. In 35 multivariable analysis, the class of CRP level (defined by median CRP levels of 96 mg/l) was the sole 36 independent risk factor of VRC overdose (p < 0.01). Patients with CRP levels > 96 mg/l had a 27-fold 37 (IC 95%: [6-106]) higher risk of VRC overdose than patients with CRP levels ≤ 96 mg/l. 38Conclusion: This study demonstrates that inflammatory status, assessed by CRP levels, is the main 39 risk factor of VRC overdose in French hematological patients, whereas pharmacogenetic 40 determinants do not appear to be involved. 41 42