Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen
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.
Authors
- Radojka M. Savić (ORCID: https://orcid.org/0000-0003-3143-5579)
- Andrew Garcia (ORCID: https://orcid.org/0000-0003-1670-9818)
- Rokeya Tasneen
- Veronique Anne Dartois (ORCID: https://orcid.org/0000-0001-9470-5009)
- Heena Soni (ORCID: https://orcid.org/0009-0003-9727-9334)
- Marjorie Z. Imperial (ORCID: https://orcid.org/0000-0001-7434-3012)
- Belén Pérez Solans (ORCID: https://orcid.org/0000-0003-4621-5480)
- Sandeep Tyagi (ORCID: https://orcid.org/0000-0002-6066-5392)
- Kristina M. Bigelow (ORCID: https://orcid.org/0000-0002-1630-2121)
- Jacqueline P. Ernest (ORCID: https://orcid.org/0000-0002-7664-7287)
- Eric L. Nuermberger (ORCID: https://orcid.org/0000-0003-1440-9889)
- Jansy Passiflora Sarathy (ORCID: https://orcid.org/0000-0002-1532-146X)
- Natasha Strydom (ORCID: https://orcid.org/0000-0002-0929-0783)
- Martin Gengenbacher (ORCID: https://orcid.org/0000-0002-0208-5920)
- Qianwen Wang (ORCID: https://orcid.org/0000-0001-9211-3974)
- Tian J. Yang (ORCID: https://orcid.org/0000-0001-7392-6398)
- Min Xie (ORCID: https://orcid.org/0000-0002-9770-5351)
- Matthew Zimmerman (ORCID: https://orcid.org/0000-0002-6229-0571)
Institutions
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- TB Alliance (US)
- Hackensack Meridian Health (US)
- Center for Discovery (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-25
- DOI
- https://doi.org/10.1038/s41467-024-50781-4
- Citations
- 14
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 5.45