Department of Pharmaceutics, University of Washingtongrid.34477.33, Seattle, Washington, USA.
Calibr, The Scripps Research Institute, La Jolla, California, USA.
Antimicrob Agents Chemother. 2022 Jan 18;66(1):e0156021. doi: 10.1128/AAC.01560-21. Epub 2021 Nov 8.
Infection with spp. can cause severe diarrhea, leading to long-term adverse impacts and even death in malnourished children and immunocompromised patients. The only FDA-approved drug for treating cryptosporidiosis, nitazoxanide, has limited efficacy in the populations impacted the most by the diarrheal disease, and safe, effective treatment options are urgently needed. Initially identified by a large-scale phenotypic screening campaign, the antimycobacterial therapeutic clofazimine demonstrated great promise in both and preclinical models of infection. Unfortunately, a phase 2a clinical trial in HIV-infected adults with cryptosporidiosis did not identify any clofazimine treatment effect on infection burden or clinical outcomes. To explore whether clofazimine's lack of efficacy in the phase 2a trial may have been due to subtherapeutic clofazimine concentrations, a pharmacokinetic/pharmacodynamic modeling approach was undertaken to determine the relationship between clofazimine concentrations and treatment effects in multiple preclinical infection models. Exposure-response relationships were characterized using and logistic models, which allowed predictions of efficacious clofazimine concentrations for the control and reduction of disease burden. After establishing exposure-response relationships for clofazimine treatment of infection in our preclinical model studies, it was unmistakable that the clofazimine levels observed in the phase 2a study participants were well below concentrations associated with anti- efficacy. Thus, despite a dosing regimen above the highest doses recommended for mycobacterial therapy, it is very likely the lack of treatment effect in the phase 2a trial was at least partially due to clofazimine concentrations below those required for efficacy against cryptosporidiosis. It is unlikely that clofazimine will provide a remedy for the large number of cryptosporidiosis patients currently without a viable treatment option unless alternative, safe clofazimine formulations with improved oral absorption are developed. (This study has been registered in ClinicalTrials.gov under identifier NCT03341767.).
spp. 感染可导致严重腹泻，在营养不良的儿童和免疫功能低下的患者中可导致长期不良后果，甚至死亡。唯一经美国食品药品监督管理局批准用于治疗隐孢子虫病的药物硝唑尼特在受腹泻病影响最严重的人群中的疗效有限，因此迫切需要安全有效的治疗选择。氯法齐明最初是通过大规模表型筛选发现的，在 和 感染的临床前模型中都显示出巨大的应用潜力。不幸的是，在感染 HIV 的隐孢子虫病成人中进行的 2a 期临床试验并未发现氯法齐明对 感染负担或临床结局有任何治疗作用。为了探究氯法齐明在 2a 期临床试验中无效是否是由于其血药浓度未达到治疗效果，采用药代动力学/药效学建模方法来确定氯法齐明浓度与多种临床前感染模型中治疗效果之间的关系。采用 和逻辑模型来描述暴露-反应关系，从而可以预测控制和减少疾病负担的有效氯法齐明浓度。在我们的临床前模型研究中建立了氯法齐明治疗 感染的暴露-反应关系后，很明显，在 2a 期研究参与者中观察到的氯法齐明水平远低于与抗 疗效相关的浓度。因此，尽管该剂量方案高于推荐用于抗分枝杆菌治疗的最高剂量，但在 2a 期试验中缺乏治疗效果至少部分是由于氯法齐明浓度低于抗隐孢子虫病所需的浓度。除非开发出具有更好口服吸收的替代、安全的氯法齐明制剂，否则氯法齐明不太可能为目前尚无可行治疗方案的大量隐孢子虫病患者提供治疗方法。（本研究已在 ClinicalTrials.gov 注册，登记号为 NCT03341767。）。
