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

Abstract

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 (AUC24) 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 (Cmin) was 0.11 ± 0.16 mg/liter, and hydroxyitraconazole Cmin was 0.13 ± 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log10 CFU/ml/h, respectively. There were no associations between itraconazole Cmin/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.

• Authors: Katharine E Stott, Thuy Le, Thu Nguyen, Sarah Whalley, Jennifer Unsworth, Vo Trieu Ly, Ruwanthi Kolamunnage-Dona, William Hope
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 65 Issue 11 Pg. e0063621 (10 18 2021) ISSN: 1098-6596 [Electronic] United States
• PMID: 34370587 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Itraconazole

Topics

• Antifungal Agents (therapeutic use)
• Humans
• Itraconazole (therapeutic use)
• Mycoses (drug therapy)
• Talaromyces