Repeated voriconazole therapeutic drug monitoring in hospitalised patients: a real-world cohort study of out-of-range exposure and concentration response to dose adjustment.

BACKGROUND: Longitudinal evidence on repeated voriconazole therapeutic drug monitoring (TDM) in selected hospitalised patients is limited. We examined factors associated with out-of-range exposure and described concentration changes after dose adjustment in hospitalised patients undergoing repeated TDM. METHODS: This retrospective, single-centre, longitudinal cohort study included hospitalised adults who received voriconazole and contributed at least three valid TDM episodes. Trough concentrations were classified as subtherapeutic (<1.0 μg/mL), in range (1.0-5.0 μg/mL), or supratherapeutic (>5.0 μg/mL). Bayesian mixed-effects logistic regression with weakly informative priors and patient-level random intercepts identified factors associated with each direction of out-of-range exposure. Adjacent TDM pairs with a documented dose change were analysed for return to range. RESULTS: A total of 140 patients contributed 497 episodes; 72 (14.5%) were subtherapeutic and 145 (29.2%) supratherapeutic. In the 445-episode complete-case models, subtherapeutic exposure was associated with rifampin-like inducer co-administration (OR 16.48, 95% CrI 2.38-139.44) and lower daily dose (OR 0.45 per 100 mg, 95% CrI 0.29-0.66), whereas supratherapeutic exposure was associated with the CYP2C19 poor-metaboliser phenotype (OR 5.24, 95% CrI 1.76-16.66), higher log-CRP (OR 1.69, 95% CrI 1.23-2.40), and higher total bilirubin (OR 1.09 per 10 μmol/L, 95% CrI 1.03-1.15). Concentrations returned to range after 7 of 12 (58.3%) clinically concordant dose increases, but after only 26 of 75 (34.7%) clinically concordant dose decreases. CONCLUSION: In hospitalised patients undergoing repeated voriconazole TDM, the factors associated with subtherapeutic and supratherapeutic exposure differed by direction. After dose reduction, supratherapeutic concentrations frequently did not return to range; this descriptive pattern is compatible with several contributors, including resampling before a new steady state and voriconazole's nonlinear metabolism. These findings may help clinicians interpret repeated TDM results in complex inpatient settings.