Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy, University of California, San Francisco, CA, USA.
Center for Tuberculosis Research, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Nat Commun. 2024 Aug 25;15(1):7311. doi: 10.1038/s41467-024-50781-4.
TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.
TBI-223 是一种新型的噁唑烷酮类药物，旨在与贝达喹啉和普托马尼（BPaL）联合使用时，比利奈唑胺具有更好的疗效和安全性。我们旨在优化 BPaL 方案中 TBI-223 的剂量，以提高治疗效果。TBI-223 用于临床前单药治疗、多药治疗和病变渗透实验，以描述其疗效和安全性。建立了一个包含临床前实验和 4 项临床试验（NCT00396084、NCT02333799、NCT03086486、NCT00816426）的利奈唑胺和 BPaL 数据的转化平台，用于验证该框架。TBI-223 的临床前和 I 期数据（NCT03758612）被应用于转化框架，以预测临床结果并优化 TBI-223 与贝达喹啉和普托马尼的联合用药剂量。结果表明，每天使用 1200-2400 毫克 TBI-223 可能达到与 BPaL 方案相当的疗效，预计>90%的患者在两个月内达到培养转化。
