Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen

Natasha Strydom, Jacqueline P. Ernest, Marjorie Imperial, Belén P. Solans, Qianwen Wang, Rokeya Tasneen, Sandeep Tyagi, Heena Soni, Andrew Garcia, Kristina Bigelow, Martin Gengenbacher, Matthew Zimmerman, Min Xie, Jansy P. Sarathy, Tian J. Yang, Véronique Dartois, Eric L. Nuermberger and Radojka M. Savic ()
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Natasha Strydom: University of California
Jacqueline P. Ernest: University of California
Marjorie Imperial: University of California
Belén P. Solans: University of California
Qianwen Wang: University of California
Rokeya Tasneen: Johns Hopkins University
Sandeep Tyagi: Johns Hopkins University
Heena Soni: Johns Hopkins University
Andrew Garcia: Johns Hopkins University
Kristina Bigelow: Johns Hopkins University
Martin Gengenbacher: Hackensack Meridian Health
Matthew Zimmerman: Hackensack Meridian Health
Min Xie: Hackensack Meridian Health
Jansy P. Sarathy: Hackensack Meridian Health
Tian J. Yang: TB Alliance
Véronique Dartois: Hackensack Meridian Health
Eric L. Nuermberger: Johns Hopkins University
Radojka M. Savic: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50781-4

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