Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, South Africa.
Clin Infect Dis. 2018 Nov 28;67(suppl_3):S284-S292. doi: 10.1093/cid/ciy610.
In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic (PK) study. We sought to determine if PK variability played a role in patient outcomes.
Patients recruited in the trial were followed for 24 months, and relapse ascertained using spoligotyping. Blood was drawn for drug concentrations on 2 separate days during the first 2 months of therapy, and compartmental PK analyses was performed. Failure to attain sustained sputum culture conversion at the end of treatment, relapse, or death during follow-up defined therapy failure. In addition to standard statistical analyses, we utilized an ensemble of machine-learning methods to identify patterns and predictors of therapy failure from among 27 clinical and laboratory features.
Of 126 patients, 95 (75%) had favorable outcomes and 19 (15%) failed therapy, relapsed, or died. Pyrazinamide and rifampicin peak concentrations and area under the concentration-time curves (AUCs) were ranked higher (more important) than gatifloxacin AUCs. The distribution of individual drug concentrations and their ranking varied significantly between South African and West African trial sites; however, drug concentrations still accounted for 31% and 75% of variance of outcomes, respectively. We identified a 3-way antagonistic interaction of pyrazinamide, gatifloxacin, and rifampicin concentrations. These negative interactions disappeared if rifampicin peak concentration was above 7 mg/L.
Concentration-dependent antagonism contributed to death, relapse, and therapy failure but was abrogated by high rifampicin concentrations. Therefore, increasing both rifampin and gatifloxacin doses could improve outcomes.
NCT00216385.
在 OFLOTUB 试验的实验组中，加替沙星取代了乙胺丁醇，用于治疗敏感型肺结核的标准 4 个月疗程。该研究包括一个嵌套的药代动力学（PK）研究。我们试图确定 PK 变异性是否在患者结局中起作用。
在试验中招募的患者接受了 24 个月的随访，并通过 spoligotyping 确定复发情况。在治疗的前 2 个月的 2 天内分别抽取血液进行药物浓度检测，并进行房室 PK 分析。治疗结束时未能持续痰培养转阴、复发或随访期间死亡定义为治疗失败。除了标准的统计分析外，我们还利用了一组机器学习方法，从 27 个临床和实验室特征中识别出治疗失败的模式和预测因素。
在 126 名患者中，95 名（75%）有良好的结局，19 名（15%）治疗失败、复发或死亡。吡嗪酰胺和利福平的峰浓度和浓度-时间曲线下面积（AUC）排名较高（更重要），而加替沙星 AUC 排名较低。南非和西非试验点的个体药物浓度分布及其排名差异显著；然而，药物浓度分别解释了结局的 31%和 75%的方差。我们发现吡嗪酰胺、加替沙星和利福平浓度之间存在三向拮抗相互作用。如果利福平的峰浓度超过 7mg/L，这种负相互作用就会消失。
浓度依赖性拮抗作用导致死亡、复发和治疗失败，但高利福平浓度可以消除这种作用。因此，增加利福平与加替沙星的剂量可以改善结局。
NCT00216385。
