Population Pharmacokinetics and Pharmacodynamics of Itraconazole for Disseminated Infection Caused by Talaromyces marneffei

First-line treatment of talaromycosis with amphotericin B deoxycholate (DAmB) is labor-intensive and toxic. Itraconazole is an appealing alternative antifungal agent. Pharmacokinetic data were obtained from 76 patients who were randomized to itraconazole in the Itraconazole versus Amphotericin B for Talaromycosis (IVAP) trial. Plasma levels of itraconazole and its active metabolite, hydroxyitraconazole, were analyzed alongside longitudinal fungal CFU counts in a population model. Itraconazole and hydroxyitraconazole pharmacokinetic variability was considerable, with areas under the concentration-time curve over 24 h (AUC(24)) of 3.34 +/- 4.31 mg.h/liter and 3.57 +/- 4.46 mg.h/liter (mean +/- standard deviation), respectively. Levels of both analytes were low; itraconazole minimum concentration (C-min) was 0.11 +/- 0.16 mg/liter, and hydroxyitraconazole C-min was 0.13 6 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log(10) CFU/ml/h, respectively. There were no associations between itraconazole C-min/MIC and time to sterilization of the bloodstream (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.99 to 1.03; P = 0.43), time to death (HR, 0.99; 95% CI, 0.96 to 1.02; P = 0.77), or early fungicidal activity (EFA) (coefficient, -0.004; 95% CI, -0.010 to 0.002; P = 0.18). Similarly, there was no relationship between AUC/MIC and time to sterilization of the bloodstream (HR, 1.00; 95% CI, 0.99 to 1.00; P = 0.50), time to death (HR, 1.00; 95% CI, 0.99 to 1.00; P = 0.91), or EFA (coefficient, -0.0001; 95% CI, -0.0003 to 0.0001; P = 0.19). This study raises the possibility that the failure of itraconazole to satisfy noninferiority criteria against DAmB for talaromycosis in the IVAP trial was a pharmacokinetic and pharmacodynamic failure.