Safety, Tolerability, and Pharmacokinetics of a Novel Nitroimidazooxazole Antitubercular Agent in Healthy Adults: A Phase I Trial

Abstract

This study evaluated the safety, tolerability, and pharmacokinetics of JBD0131, a novel nitroimidazooxazole antitubercular agent, in healthy adults. We previously reported JBD0131, a novel nitroimidazooxazole antitubercular agent, which overcomes drug resistance and bioavailability limitations of existing anti-tuberculosis therapies. The clinical trial was structured into three parts: an initial single ascending dose (SAD) phase under fasting conditions, a food-effect assessment, and a final multiple ascending dose (MAD) phase conducted after meals. Among 95 enrolled participants, JBD0131 demonstrated favorable safety and tolerability across all regimens. No serious adverse events (AEs) or treatment discontinuations occurred. Treatment-emergent AE incidence was comparable to placebo without dose-dependent trends. Pharmacokinetic (PK) analysis showed that systemic exposure for JBD0131, measured by maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC), increased proportionally with the dose. The presence of food significantly enhanced the bioavailability and delayed the median time to reach peak concentration (T_max) by approximately 2 h. These findings collectively demonstrate that JBD0131 has an acceptable safety profile and predictable, linear pharmacokinetics in healthy adults. The observed food effect, which boosts systemic exposure, along with the drug's linear accumulation, supports the need for further investigation to define optimal treatment regimens for future clinical development.

Keywords

anti-tuberculosis / clinical trial / JBD0131 / safety

References

[1] https://www.who.int/teams/global-programme-on-tuberculosis-and-lung-health/tb-reports/global-tuberculosis-report-2024.

[2] A. Vasiliu, L. Martinez, R. K. Gupta, et al., “Tuberculosis Prevention: Current Strategies and Future Directions,” Clinical Microbiology and Infection 30, no. 9 (2024): 1123–1130.

[3] N. C. Howard and S. A. Khader, “Immunometabolism During Mycobacterium Tuberculosis Infection,” Trends in Microbiology 28, no. 10 (2020): 832–850.

[4] R. D. Kanabalan, L. J. Lee, T. Y. Lee, et al., “Human Tuberculosis and Mycobacterium Tuberculosis Complex: A Review on Genetic Diversity, Pathogenesis and Omics Approaches in Host Biomarkers Discovery,” Microbiological Research 246 (2021): 126674.

[5] J. Ben Amar, B. Dhahri, H. Aouina, et al., “Treatment of tuberculosis,” Revue De Pneumologie Clinique 71, no. 2-3 (2015): 122–129.

[6] C. E. Flynn and J. Guarner, “Emerging Antimicrobial Resistance,” Modern Pathology 36, no. 9 (2023): 100249.

[7] S. Bertagnolio, Z. Dobreva, C. M. Centner, et al., “WHO Global Research Priorities for Antimicrobial Resistance in human Health,” The Lancet Microbe 5, no. 11 (2024): 100902.

[8] E. Variava and N. Martinson, “Drug-Resistant Tuberculosis: The Rise of the Monos,” The Lancet Infectious Diseases 18, no. 7 (2018): 705–706.

[9] A. N. Unissa, S. Subbian, L. E. Hanna, and N. Selvakumar, “Overview on Mechanisms of Isoniazid Action and Resistance in Mycobacterium Tuberculosis,” Infection, Genetics and Evolution 45 (2016): 474–492.

[10] E. A. Kendall, T. Cohen, C. D. Mitnick, and D. W. Dowdy, “Second Line Drug Susceptibility Testing to Inform the Treatment of Rifampin-Resistant Tuberculosis: A Quantitative Perspective,” International Journal of Infectious Diseases 56 (2017): 185–189, https://doi.org/10.1016/j.ijid.2016.12.010.

[11] S. G. Murphy, C. Smith, P. Lapierre, et al., “Direct Detection of Drug-Resistant Mycobacterium Tuberculosis Using Targeted Next Generation Sequencing,” Front Public Health 11 (2023): 1206056.

[12] S. Moadebi, C. K. Harder, M. J. Fitzgerald, K. R. Elwood, and F. Marra, “Fluoroquinolones for the Treatment of Pulmonary Tuberculosis,” Drugs 67, no. 14 (2007): 2077–2099.

[13] K. Dheda, K. C. Chang, L. Guglielmetti, et al., “Clinical Management of Adults and Children With Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis,” Clinical Microbiology and Infection 23, no. 3 (2017): 131–140.

[14] S. Mase, T. Chorba, S. Parks, et al., “Bedaquiline for the Treatment of Multidrug-Resistant Tuberculosis in the United States,” Clinical Infectious Diseases 71, no. 4 (2020): 1010–1016.

[15] S. Andrei, G. Droc, and G. Stefan, “FDA Approved Antibacterial Drugs: 2018-2019,” Discoveries (Craiova) 7, no. 4 (2019): e102.

[16] N. Riccardi, F. Del Puente, F. Magne, L. Taramasso, and D. I. B. A. Bedaquiline, “A New Hope for Shorter and Better Anti-Tuberculosis Regimens,” Recent Patents on Anti-Infective Drug Discovery 13, no. 1 (2018): 3–11.

[17] C. D. Tweed, R. Dawson, D. A. Burger, et al., “Bedaquiline, Moxifloxacin, Pretomanid, and Pyrazinamide During the First 8 Weeks of Treatment of Patients With Drug-Susceptible or Drug-Resistant Pulmonary Tuberculosis: A Multicentre, Open-Label, Partially Randomised, Phase 2b Trial,” Lancet Respiratory Medicine 7, no. 12 (2019): 1048–1058.

[18] C. Padmapriyadarsini, B. Devaleenal, C. Ponnuraja, et al., “Randomised Trial to Evaluate the Effectiveness and Safety of Varying Doses of Linezolid With Bedaquiline and Pretomanid in Adults With Pre-Extensively Drug-Resistant or Treatment Intolerant/Non-Responsive Multidrug-resistant Pulmonary Tuberculosis: Study Protocol,” BMJ Open 12, no. 8 (2022): e058606.

[19] A. H. Diacon, R. Dawson, M. Hanekom, et al., “Early Bactericidal Activity of Delamanid (OPC-67683) in Smear-Positive Pulmonary Tuberculosis Patients,” International Journal of Tuberculosis and Lung Disease 15, no. 7 (2011): 949–954.

[20] X. Tao, C. Gao, Z. G. Huang, et al., “Discovery and Evaluation of Novel Nitrodihydroimidazooxazoles as Promising Anti-Tuberculosis Agents,” Bioorganic & Medicinal Chemistry Letters 29, no. 17 (2019): 2511–2515.

[21] N. Mohammadnabi, J. Shamseddin, M. Emadi, et al., “Mycobacterium Tuberculosis: The Mechanism of Pathogenicity, Immune Responses, and Diagnostic Challenges,” Journal of Clinical Laboratory Analysis 38, no. 23 (2024): e25122.

[22] G. A. Goig, E. M. Windels, C. Loiseau, et al., “Ecology, Global Diversity and Evolutionary Mechanisms in the Mycobacterium Tuberculosis Complex,” Nature Reviews Microbiology 23, no. 9 (2025): 602–614.

[23] N. Dookie, S. L. Ngema, R. Perumal, N. Naicker, N. Padayatchi, and K. Naidoo, “The Changing Paradigm of Drug-Resistant Tuberculosis Treatment: Successes, Pitfalls, and Future Perspectives,” Clinical Microbiology Reviews 35, no. 4 (2022): e0018019.

[24] M. G. G. Sturkenboom, A. G. Martson, E. M. Svensson, et al., “Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs,” Clinical Pharmacokinetics 60, no. 6 (2021): 685–710.

[25] E. H. Ignatius, M. T. Abdelwahab, B. Hendricks, et al., “Pretomanid Pharmacokinetics in the Presence of Rifamycins: Interim Results From a Randomized Trial Among Patients With Tuberculosis,” Antimicrobial Agents and Chemotherapy 65, no. 2 (2021).

[26] L. Tanneau, M. O. Karlsson, A. H. Diacon, et al., “Population Pharmacokinetics of Delamanid and Its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered With Bedaquiline,” Clinical Pharmacokinetics 61, no. 8 (2022): 1177–1185.

[27] D. H. Salinger, V. Subramoney, D. Everitt, and J. R. Nedelman, “Population Pharmacokinetics of the Antituberculosis Agent Pretomanid,” Antimicrobial Agents and Chemotherapy 63, no. 10 (2019).

[28] R. Holm, A. Mullertz, and H. Mu, “Bile Salts and Their Importance for Drug Absorption,” International Journal of Pharmaceutics 453, no. 1 (2013): 44–55.

[29] N. Pavlovic, S. Golocorbin-Kon, M. Ethanic, et al., “Bile Acids and Their Derivatives as Potential Modifiers of Drug Release and Pharmacokinetic Profiles,” Frontiers in Pharmacology 9 (2018): 1283.

[30] M. Markovic, S. Ben-Shabat, A. Aponick, E. M. Zimmermann, and A. Dahan, “Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics,” International Journal of Molecular Sciences 21, no. 9 (2020).

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