Drug–drug interaction between itraconazole capsule and efavirenz in adults with HIV for talaromycosis treatment

Abstract

Abstract Objectives To assess the pharmacokinetic of itraconazole capsule formulation and its active metabolite, hydroxyitraconazole, in adults with HIV diagnosed with talaromycosis in an endemic area, and to evaluate the drug–drug interaction between itraconazole/hydroxyitraconazole (ITC/OH-ITC) and efavirenz. Methods Open-label, single arm, sequential pharmacokinetic study. Eligible subjects were adults with HIV, ≥18 years old, with confirmed talaromycosis, initiating itraconazole capsule as part of standard talaromycosis treatment, in whom efavirenz-based ART was anticipated. Steady-state pharmacokinetic assessments (pre-dose and at 1, 3, 4, 5, 6, 8 and 12 h post dose) were performed for itraconazole/hydroxyitraconazole without and with efavirenz use. Mid-dose efavirenz concentrations were also assessed. Pharmacokinetics parameters were calculated using non-compartmental analysis. Results Ten subjects (70% male) were enrolled. At entry, median (range) age was 29.5 years (22–64), and CD4 cell count was 18.0 (1–39) cells/mm3. Geometric mean (95% CI) of itraconazole and hydroxyitraconazole AUC0–12 without efavirenz were 9097 (6761–12 239) and 11 705 (8586-15 959) ng·h/mL, respectively, with a median metabolic ratio of OH-ITC : ITC of 1.3 (95% CI 0.9–1.9). Intra-subject comparison revealed that both itraconazole and hydroxyitraconazole exposures were significantly reduced with concomitant efavirenz use, with the mean AUC0–12 of itraconazole and hydroxyitraconazole being 86% (71%–94%) and 84% (64%–97%) lower, respectively. With efavirenz, itraconazole trough concentrations were also below the recommended therapeutic level (0.5 μg/mL). All subjects had mid-dose efavirenz concentrations >1000 ng/mL. Conclusions Concomitant administration of itraconazole capsule with efavirenz significantly reduced itraconazole and hydroxyitraconazole exposures. The clinical impact of this drug–drug interaction on talaromycosis treatment or prophylaxis in the era of potent ART needs further evaluation.