Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen
Natasha Strydom, Jacqueline P. Ernest, Marjorie Z. Imperial, Belén P. Solans, Qianwen Wang, Rokeya Tasneen, Sandeep Tyagi, Heena Soni, Andrew Garcia, Kristina M. Bigelow, Martin Gengenbacher, Matthew Zimmerman, Min Xie, Jansy P. Sarathy, Tian J. Yang, Véronique Dartois, Eric L. Nuermberger, Radojka M. Savić
Abstract
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.