Bustion Annamarie E, Ernest Jacqueline P, Kaya Firat, Silva Connie, Sarathy Jansy, Blanc Landry, Imperial Marjorie, Gengenbacher Martin, Xie Min, Zimmerman Matthew D, Robertson Gregory T, Weiner Danielle, Via Laura E, Barry Clifton E, Savic Radojka M, Dartois Véronique
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco.
Center for Discovery and Innovation.
J Infect Dis. 2025 Sep 15;232(3):e431-e441. doi: 10.1093/infdis/jiaf303.
Cavitary tuberculosis is difficult to cure and constitutes a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug-resistant tuberculosis, but emergence of resistance threatens the sustainability of its success. We designed site-of-disease pharmacokinetic studies to spatially resolve the penetration of bedaquiline, and 2 next-generation diarylquinolines, TBAJ876 and TBAJ587, in cavities.
Rabbits with established cavitary tuberculosis received the study drugs. A laser-capture microdissections scheme was developed to measure drug concentrations as a function of distance from blood supply in caseum. To simulate drug coverage in patient cavities, the data were modeled, and parameter estimates were linked to clinical plasma pharmacokinetic models.
Pharmacokinetic-pharmacodynamic simulations in caseum revealed that bedaquiline reaches steady state and efficacious concentrations in deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ876 and TBAJ587, achieve bactericidal concentrations in caseum layers more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline.
The slow kinetics of diffusion of bedaquiline into and out of caseum creates spatiotemporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ587 and TBAJ876 predict reduced opportunities for resistance development.
空洞型肺结核难以治愈且是复发部位。贝达喹啉是治疗耐多药结核病的神奇药物，但耐药性的出现威胁到其成功的可持续性。我们设计了疾病部位药代动力学研究，以在空间上解析贝达喹啉以及两种下一代二芳基喹啉TBAJ876和TBAJ587在空洞中的渗透情况。
患有已确诊空洞型肺结核的兔子接受研究药物。制定了激光捕获显微切割方案，以测量药物浓度作为距干酪样坏死物血供距离的函数。为模拟患者空洞中的药物覆盖情况，对数据进行建模，并将参数估计值与临床血浆药代动力学模型相联系。
干酪样坏死物中的药代动力学 - 药效学模拟显示，贝达喹啉在数周至数月后在深部干酪样坏死物中达到稳态和有效浓度，并在治疗结束后长达3年保持在亚治疗浓度。与贝达喹啉相比，TBAJ876和TBAJ587在干酪样坏死物层中更快达到杀菌浓度，并缩短治疗后亚最佳浓度的窗口期。
贝达喹啉进出干酪样坏死物的缓慢扩散动力学产生了亚治疗浓度的时空窗口。TBAJ587和TBAJ876的疾病部位模拟预测耐药性发展的机会减少。
