Population Pharmacokinetics and Exposure-Response Analysis of Voriconazole in ICU and Non-ICU Hospitalized Adults

Abstract

Background Voriconazole has marked pharmacokinetic variability and a narrow therapeutic window, making individualized dosing difficult. Published population pharmacokinetic (PopPK) models most derive from ICU or general-ward patients, and exposure-response studies are limited. This retrospective study aimed to characterize voriconazole PopPK and exposure-response analysis in real‑world hospitalized patients containing both ICU and non-ICU patients. Methods Adults receiving voriconazole with therapeutic drug monitoring were included. PopPK analysis used NONMEM. Demographic variables and lab biomarkers were screened. Monte Carlo simulations were used to show covariates’ effect on drug exposure under standard dosing regimen. Model-derived voriconazole exposure was linked to treatment outcome and adverse drug reactions (ADR) using logistic regression. Results 292 patients with 473 voriconazole concentrations were included. A one-compartment model with first-order elimination adequately described the data, with estimated population clearance, volume of distribution and derived half-life of 3.3 L/h, 92 L and 19 h, respectively. Voriconazole clearance increased with body weight and albumin and decreased with age, CRP, total bilirubin, and serum creatinine. These covariates decrease clearance inter-individual variability from 44.5% to 32.6 %; all parameters fell within bootstrap 90% interval. With a standard regimen 300 mg every 12 h for first day then 200 mg every 12 h, simulations showed underexposure in younger patients without organ dysfunction and overexposure in elderly patients with elevated CRP, total bilirubin or serum creatinine. In multivariable logistic regression, excessively high average concentration (Cavg) derived by model was associated with treatment failure (adjusted odds ratio 1.45 per mg/L, 95% CI 1.07–2.03, p=0.019). Cavg was not significant, whereas older age was associated with higher ADR risk (adjusted odds ratio 1.05, 95% CI 1.01–1.10). Conclusion Age, CRP, albumin, total bilirubin and creatinine explain clinically relevant variability in voriconazole exposure and indicate that a fixed regimen may not benefit all patients. The association between higher Cavg and treatment failure is observational and needs further prospective studies and external validations.