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Inhaled Adjunct Therapy with Second-Line Drug Candidates for Dose Reduction in Chemotherapeutic Regimens for Multi-drug-Resistant Tuberculosis

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Abstract

Chemotherapy of multi-drug-resistant tuberculosis (TB) requires prolonged administration of multiple drugs. We investigated whether pulmonary delivery of minute doses of drugs, along with reduced oral doses of the same agents, would affect preclinical efficacy. We prepared dry powder inhalation (DPI) formulations comprising sutezolid (SUT), the second-generation pretomanid analog TBA-354 (TBA), or a fluorinated derivative of TBA-354 (32,625) in a matrix of the biodegradable polymer poly(l-lactide). We established formulation characteristics, doses inhaled by healthy mice, and preclinical efficacy in a mouse model of TB. Oral doses of 100 mg/kg/day or DPI doses of 0.25–0.5 mg/kg/day of drugs SUT, TBA-354, or 32,625 administered over 28 days were sub-optimally effective in reducing lung and spleen burden of Mycobacterium tuberculosis (Mtb) in infected mice. The addition of 0.25–0.5 mg/kg/day of SUT, TBA-354, or 32,625 as DPI to oral doses of 50 mg/kg/day was non-inferior in clearing Mtb from the lungs of infected mice. We concluded that adjunct therapy with inhaled second-line agents has the potential to reduce the efficacious oral dose.

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Acknowledgements

This is CDRI Manuscript Number 05/2023/AM. Compounds used in this work were donated by Prof. Andrew M. Thompson, Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1023, New Zealand.

Funding

This work was supported by the Indian Council of Medical Research (AMR/IN/112/2017-ECD-II to A. M.) and the Norwegian Research Council (Frimedbio 275873 and Bedrehelse 273319 to G. G.). S.V., A.S., R.B., D.V.S.R., H.S., T.R., K.V., S.K.R., L.A., and LR received fellowships from CSIR, ICMR, and UGC (India).

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Authors and Affiliations

  1. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, UP, India

    Sonia Verma, Ashish Srivastava, Reena Bharti, D. V. Siva Reddy, Hasham Shafi Sofi, Trisha Roy, Khushboo Verma, Sunil K. Raman, Lubna Azmi, Lipika Ray, Madhav N. Mugale & Amit Misra

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, UP, India

    Sonia Verma, Ashish Srivastava, D. V. Siva Reddy, Trisha Roy, Khushboo Verma, Madhav N. Mugale & Amit Misra

  3. Department of Biosciences, University of Oslo, 0316, Oslo, Norway

    Nils-Jorgen K. Dal & Gareth Griffiths

  4. National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, 282004, UP, India

    Amit K. Singh

  5. CSIR-Indian Institute of Toxicology, Lucknow, 226001, UP, India

    Jyotsna Singh

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  1. Sonia Verma
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Contributions

SV, N-JKD, AS, RB, DVSR, HS, TR, KV, SKR, LA, LR, MNM, AKS, JS: conducted the experiments, analyzed the data, and interpreted the results. LA, LR, MNM, AKS, JS, AMT, GG, AM: supervised the experiments, analyzed the data, interpreted the results. SV, RB, LA, LR, MNM, AKS, JS, AMT, GG, AM: wrote and edited the manuscript. GG, AM: secured funding.

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Correspondence to Gareth Griffiths or Amit Misra.

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Verma, S., Dal, NJ.K., Srivastava, A. et al. Inhaled Adjunct Therapy with Second-Line Drug Candidates for Dose Reduction in Chemotherapeutic Regimens for Multi-drug-Resistant Tuberculosis. AAPS PharmSciTech 24, 130 (2023). https://doi.org/10.1208/s12249-023-02585-w

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