Antimicrobial Pharmacodynamics and Therapeutics, Department of Molecular and Clinical Pharmacology, Institute of Systems, Molecular and Integrative Biology, University of Liverpoolgrid.10025.36, United Kingdom.
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0063621. doi: 10.1128/AAC.00636-21. Epub 2021 Aug 9.
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) 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 () was 0.11 ± 0.16 mg/liter, and hydroxyitraconazole was 0.13 ± 0.17 mg/liter. The mean maximal rates of drug-induced killing were 0.206 and 0.208 log CFU/ml/h, respectively. There were no associations between itraconazole /MIC and time to sterilization of the bloodstream (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.99 to 1.03; = 0.43), time to death (HR, 0.99; 95% CI, 0.96 to 1.02; = 0.77), or early fungicidal activity (EFA) (coefficient, -0.004; 95% CI, -0.010 to 0.002; = 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; = 0.50), time to death (HR, 1.00; 95% CI, 0.99 to 1.00; = 0.91), or EFA (coefficient, -0.0001; 95% CI, -0.0003 to 0.0001; = 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.
伏立康唑是治疗足放线病菌病的一线药物，但这种药物副作用大，且治疗过程繁琐。伊曲康唑是一种很有前途的抗真菌药物。本研究对参加伊曲康唑对比两性霉素 B 去氧胆酸盐治疗足放线病菌病（IVAP）试验的 76 名患者进行了药代动力学数据分析，评估了伊曲康唑及其活性代谢产物羟基伊曲康唑的血药浓度，同时还分析了纵向真菌 CFU 计数的群体模型。研究结果显示，伊曲康唑和羟基伊曲康唑的药代动力学差异较大，24 小时浓度时间曲线下面积（AUC）分别为 3.34±4.31mg·h/L 和 3.57±4.46mg·h/L（平均值±标准差）。两种分析物的水平都较低；伊曲康唑的最低浓度（）为 0.11±0.16mg/L，羟基伊曲康唑为 0.13±0.17mg/L。药物诱导杀伤的最大平均速率分别为 0.206 和 0.208 log CFU/ml/h。伊曲康唑/ MIC 与血培养转阴时间（风险比[HR]，1.01；95%置信区间[CI]，0.99 至 1.03； = 0.43）、死亡时间（HR，0.99；95%CI，0.96 至 1.02； = 0.77）或早期杀菌活性（EFA）（系数，-0.004；95%CI，-0.010 至 0.002； = 0.18）之间均无关联。同样，AUC/MIC 与血培养转阴时间（HR，1.00；95%CI，0.99 至 1.00； = 0.50）、死亡时间（HR，1.00；95%CI，0.99 至 1.00； = 0.91）或 EFA（系数，-0.0001；95%CI，-0.0003 至 0.0001； = 0.19）之间也没有关系。本研究提示，伊曲康唑治疗足放线病菌病的非劣效性未能达到两性霉素 B 去氧胆酸盐的标准，可能是由于药代动力学和药效动力学方面的失败。
