Factors influencing plasma concentration of voriconazole and voriconazole- N-oxide in younger adult and elderly patients

Background: Voriconazole (VCZ) metabolism is influenced by many factors. Identifying independent influencing factors helps optimize VCZ dosing regimens and maintain its trough concentration (C(0)) in the therapeutic window. Methods: We conducted a prospective study investigating independent factors influencing VCZ C(0) and the VCZ C(0) to VCZ N-oxide concentration ratio (C(0)/C(N)) in younger adults and elderly patients. A stepwise multivariate linear regression model, including the IL-6 inflammatory marker, was used. The receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive effect of the indicator. Results: A total of 463 VCZ C(0) were analyzed from 304 patients. In younger adult patients, the independent factors that influenced VCZ C(0) were the levels of total bile acid (TBA) and glutamic-pyruvic transaminase (ALT) and the use of proton-pump inhibitors. The independent factors influencing VCZ C(0)/C(N) were IL-6, age, direct bilirubin, and TBA. The TBA level was positively associated with VCZ C(0) (ρ = 0.176, p = 0.019). VCZ C(0) increased significantly when the TBA levels were higher than 10 μmol/L (p = 0.027). ROC curve analysis indicated that when the TBA level ≥4.05 μmol/L, the incidence of a VCZ C(0) greater than 5 μg/ml (95% CI = 0.54–0.74) (p = 0.007) increased. In elderly patients, the influencing factors of VCZ C(0) were DBIL, albumin, and estimated glomerular filtration rate (eGFR). The independent factors that affected VCZ C(0)/C(N) were eGFR, ALT, γ-glutamyl transferase, TBA, and platelet count. TBA levels showed a positive association with VCZ C(0) (ρ = 0.204, p = 0.006) and C(0)/C(N) (ρ = 0.342, p < 0.001). VCZ C(0)/C(N) increased significantly when TBA levels were greater than 10 μmol/L (p = 0.025). ROC curve analysis indicated that when the TBA level ≥14.55 μmol/L, the incidence of a VCZ C(0) greater than 5 μg/ml (95% CI = 0.52–0.71) (p = 0.048) increased. Conclusion: TBA level may serve as a novel marker for VCZ metabolism. eGFR and platelet count should also be considered when using VCZ, especially in elderly patients.