Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data

利福喷丁 利福霉素 药代动力学 利福平 医学 药理学 肺结核 结核分枝杆菌 利福平 抗生素 药效学 药品 加药 内科学 病理 潜伏性肺结核 微生物学 生物 克拉霉素 幽门螺杆菌
作者
Dalin Rifat,Brendan Prideaux,Radojka M. Savic,Michael E. Urbanowski,Teresa L. Parsons,Brian Luna,Mark A. Marzinke,Alvaro A. Ordoñez,Vincent P. DeMarco,Sanjay Jain,Véronique Dartois,William R. Bishai,Kelly E. Dooley
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)]
卷期号:10 (435) 被引量:39
标识
DOI:10.1126/scitranslmed.aai7786
摘要

In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site-of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients ≥1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease.
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