Inflammation-driven variability in drug metabolism: Insights from voriconazole treatment of HSCT recipients

Voriconazole is commonly used to prevent fungal infections after haematopoietic stem cell transplantation (HSCT). Although its metabolism is influenced by CYP2C19 genetics and inflammation, their combined effect is rarely considered in clinical practice, and integrated analyses remain limited.

We retrospectively analysed how inflammation and CYP2C19-predicted drug-metaboliser phenotypes affect voriconazole exposure and therapeutic range attainment in 126 HSCT patients. C-reactive protein (CRP) ≥ 10 mg/L defined inflammation. A linear mixed model (LMM) assessed associations between dose-corrected voriconazole concentrations, inflammation and CYP2C19-predicted drug-metaboliser phenotype.

Dose-corrected voriconazole trough concentrations were associated with CYP2C19-predicted drug-metaboliser phenotype (LMM p = <2e-16, effect size of CYP2C19-phenotype: β = -5.99e-02-mg/L per mg voriconazole, standard error (SE) = 2.75e-02-mg/L per mg voriconazole, p = 0.0315; effect size of CRP: β = 1.54e-03-mg/L per mg voriconazole, SE = 2.79E-04-mg/L per mg voriconazole, p = 5.49e-08) and were higher during inflammation. Inflammation increased supra-therapeutic concentrations and reduced subtherapeutic levels (p = 0.0080). This effect was most pronounced for intermediate metabolisers (n = 18 with and n = 31 without inflammation) and rapid metabolisers (n = 20 with and n = 28 without inflammation), with supra-therapeutic concentration of 33% vs. 3%, and 15% vs. 0%, respectively (p = 0.02). Finally, in a longitudinal subset (n = 25), concentrations tracked inflammatory status across prior-, during and post-inflammation timepoints.

This study demonstrates inflammation and CYP2C19 genotype jointly influence voriconazole exposure and target attainment in clinical practice. These findings support intensified therapeutic drug monitoring with concurrent CRP assessment, particularly for intermediate and rapid metabolisers, to reduce the risk of supra-therapeutic voriconazole concentrations during inflammation.