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

Author

Listed:
  • 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
    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
    Hackensack Meridian Health)

  • Eric L. Nuermberger

    (Johns Hopkins University)

  • Radojka M. Savic

    (University of California)

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.

Suggested Citation

  • Natasha Strydom & Jacqueline P. Ernest & Marjorie Imperial & Belén P. Solans & Qianwen Wang & Rokeya Tasneen & Sandeep Tyagi & Heena Soni & Andrew Garcia & Kristina Bigelow & Martin Gengenbacher & Mat, 2024. "Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50781-4
    DOI: 10.1038/s41467-024-50781-4
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    References listed on IDEAS

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    1. Sebastian G. Wicha & Chunli Chen & Oskar Clewe & Ulrika S. H. Simonsson, 2017. "A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
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