Pieterman E D, van den Berg S, van der Meijden A, Svensson E M, Bax H I, de Steenwinkel J E M
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Centre, Rotterdam, the Netherlands.
Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Centre, Nijmegen, the Netherlands.
Antimicrob Agents Chemother. 2021 Mar 18;65(4). doi: 10.1128/AAC.02255-20.
Improvements in the translational value of preclinical models can allow more-successful and more-focused research on shortening the duration of tuberculosis treatment. Although the hollow-fiber infection model (HFIM) is considered a valuable addition to the drug development pipeline, its exact role has not been fully determined yet. Since the strategy of increasing the dose of rifamycins is being evaluated for its treatment-shortening potential, additional modeling is important. Therefore, we assessed increased dosing of rifampin and rifapentine in our HFIM in order to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10, and 50 mg of rifampin/kg of body weight, as well as 600 mg and 1,500 mg rifapentine, were assessed in our HFIM using the H37Rv strain. Drug activity and the emergence of drug resistance were assessed by CFU counting and subsequent mathematical modeling over 14 days, and pharmacokinetic exposures were checked. We found that increasing rifampin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity, but the clinical relevance of this observation is questionable. Moreover, for both drugs, the emergence of resistance was unrelated to exposure. In conclusion, in the simplest experimental setup, the results of the HFIM did not fully correspond to preexisting clinical data. The inclusion of additional parameters and readouts in this preclinical model could be of interest for proper assessment of the translational value of the HFIM.
提高临床前模型的转化价值可以使缩短结核病治疗疗程的研究更成功、更具针对性。尽管中空纤维感染模型（HFIM）被认为是药物研发流程中的一个有价值的补充，但其确切作用尚未完全确定。由于正在评估增加利福霉素剂量的策略对缩短治疗时间的潜力，因此进行额外的建模很重要。因此，我们在HFIM中评估了利福平及利福喷汀剂量的增加，以便更深入了解HFIM在药物研发流程中的地位。我们使用H37Rv菌株在HFIM中评估了与每日给予2.7、10和50mg/kg体重利福平以及600mg和1500mg利福喷汀相对应的总浓度和游离分数浓度。通过在14天内进行菌落形成单位计数及后续数学建模来评估药物活性和耐药性的出现，并检查药代动力学暴露情况。我们发现，将利福平暴露增加至高于标准剂量预期的水平并不会导致更高的抗分枝杆菌活性。对于利福喷汀，只有最高浓度显示出活性增加，但这一观察结果的临床相关性存疑。此外，对于这两种药物，耐药性的出现均与暴露无关。总之，在最简单的实验设置中，HFIM的结果与现有的临床数据并不完全相符。在这个临床前模型中纳入额外的参数和读数可能有助于正确评估HFIM的转化价值。
