Department of Medicine, Faculty of Medicine, Chiang Mai University, Thailand.
Research Institute for Health Sciences, Chiang Mai University, Thailand.
J Antimicrob Chemother. 2021 Mar 12;76(4):1041-1045. doi: 10.1093/jac/dkaa521.
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.
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.
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.
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.
评估伊曲康唑胶囊制剂及其活性代谢物羟基伊曲康唑在流行地区 HIV 确诊为足放线病菌病的成人中的药代动力学，并评估伊曲康唑/羟基伊曲康唑（ITC/OH-ITC）与依非韦伦之间的药物相互作用。
开放标签、单臂、连续药代动力学研究。合格的受试者为年龄≥18 岁、HIV 阳性、确诊为足放线病菌病的成年人，正在接受伊曲康唑胶囊作为标准足放线病菌病治疗的一部分，预期将使用依非韦伦进行 ART。在不使用和使用依非韦伦时进行伊曲康唑/羟基伊曲康唑的稳态药代动力学评估（用药前和用药后 1、3、4、5、6、8 和 12 小时）。还评估了中剂量依非韦伦的浓度。使用非房室分析计算药代动力学参数。
共纳入 10 名受试者（70%为男性）。入组时，中位（范围）年龄为 29.5 岁（22-64 岁），CD4 细胞计数为 18.0（1-39）个/毫米 3。不使用依非韦伦时，伊曲康唑和羟基伊曲康唑 AUC0-12 的几何均数（95%CI）分别为 9097（6761-12239）和 11705（8586-15959）ng·h/mL，代谢比 OH-ITC：ITC 中位数为 1.3（95%CI 0.9-1.9）。个体内比较显示，同时使用依非韦伦可显著降低伊曲康唑和羟基伊曲康唑的暴露量，伊曲康唑和羟基伊曲康唑 AUC0-12 的平均值分别降低 86%（71%-94%）和 84%（64%-97%）。依非韦伦使用时，伊曲康唑谷浓度也低于推荐的治疗水平（0.5μg/mL）。所有受试者的中剂量依非韦伦浓度均>1000ng/mL。
伊曲康唑胶囊与依非韦伦同时给药可显著降低伊曲康唑和羟基伊曲康唑的暴露量。在强效 ART 时代，这种药物相互作用对足放线病菌病治疗或预防的临床影响需要进一步评估。
