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

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 (Did, 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/mm(3). Geometric mean (95% CI) of itraconazole and hydroxyitraconazole AUC(0-12) 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 AUC(0-12) 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 mu g/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.