IV-065 Peter Velickovic

Translational pharmacology and dose rationale for imatinib and doramapimod as a host-directed therapy for the treatment of pulmonary tuberculosis

Peter Velickovic (1), Umberto Villani (1), Eik Hoffmann (3), Cyril Gaudin (3), Oscar Della Pasqua (1,2)

(1) Consiglio Nazionale Delle Ricerche (CNR), Rome, Italy, (2) Clinical Pharmacology and Therapeutics Group, University College London (UCL), London, United Kingdom, (3) Institut Pasteur de Lille, Lille, France.

Introduction: Tuberculosis (TB), the resulting disease of Mycobacterium tuberculosis (Mtb) infection, affects approximately 10 million people each year, despite drugs available for chemotherapy. This is due to developing resistance to current treatment regimens, such as multidrug-resistant (MDR) TB to isoniazid and rifampicin [1, 2]. To address this, an emerging strategy, host-directed therapy (HDT), is a promising avenue to bypass drug resistance. HDT compounds enhance host immune cells to control Mtb infection through immunomodulation. Combined multi-drug treatment with HDT could potentially result in more effective therapies by shortening treatment duration[3]. Imatinib (IMTB), a cancer growth blocker, and doramapimod (DOR), a p38 MAPK inhibitor, have shown HDT properties in vitro to reduce inflammatory response and granuloma formation in TB [4, 5]. No clinical studies have yet been conducted regarding HDT efficacy in conjunction with anti-TB drugs. Data indicates a correlation between severe adverse reactions and high imatinib plasma concentrations, including myelosuppression, oedema, and thrombocytopenia [6, 7].

Exploring the dose rationale in humans based on pharmacokinetic-pharmacodynamic (PKPD) modelling, simulation and extrapolation concepts, may help identifying which drugs should be prioritised for progression into clinical development.

Objective: We aim to illustrate how PKPD modelling, simulation and extrapolation principles can be used to optimise drug repurposing, specifically to guide preliminary dosing rationale for imatinib and doramapimod as HDT agents in humans. We show how PKPD data can be integrated with previously reported data to explore the therapeutic dose range and provide recommendations for the doses to be used in prospective clinical trials.

Methods: A published population PK model [8] was used to characterise the disposition of IMTB in the general population. For DOR, as no PK model was available in literature an ex novo model was developed from published PK data [9, 10]. The putative dose rationale in humans for both IMTB and DOR was investigated under the assumption that efficacious regimens should provide steady state concentrations (Css) equal or greater than concentrations predicted to be efficacious from in vitro studies.   

In vitro concentration-effect of intracellular (i.e., THP-1 human macrophages [11]) Mtb H37Rv were available for this analysis. Briefly, infected THP-1 cells were cultured for a period of 10 days after infection and treatment administration. The bacterial burden was observed at the end of such time frame. In total, 13 concentration levels were tested for IMTB and DOR, starting from 100 μM and proceeding with log2 dilutions. Effective concentrations were assumed to be associated with at least 80% reduction in CFU counts (i.e., IC80), quantified by fitting an Imax model to the available data.

Model building and simulations were conducted using NONMEM v7.5 and PsN 3.0.0. Graphical analyses were performed in R version 4.3.2.

Results: The PKPD model describing the in vitro bactericidal effect provided a good fit for the static experimental data, yielding plausible and precise potencies and, subsequently, EC80s (IMTB-4.9, DOR-0.05 mg/L, CV<20% for all parameters). For the standard clinically approved dose of IMTB, 400 mg o.d., only 9% of the virtual patient population achieved a Css above the 4.9 mg/L threshold. The dosing regimen had to be increased to 2500 mg IMTB o.d to achieve a Css above the EC80 threshold (5.1 mg/L) in 90% of the population. For DOR, model simulations predict that a 50mg o.d. yields Css values that are above in vitro DOR EC80 for at least 90% of simulated patients. This regimen aligns with clinical safety data.

Conclusions: PKPD modelling of in vitro data can be used together with extrapolation concepts and clinical trial simulations to assess the dose rationale for repurposed HDT molecules. Whereas the proposed dose of DOR has been previously shown to be safe and tolerated in humans, it has become evident that IMTB doses needed to achieve the required exposure in humans are likely to be unsafe and toxic.

We anticipate that using model-informed approaches for the evaluation and ranking of compounds to be evaluated in clinical development will contribute to reducing attrition and expediting the development of repurposed HDT candidates.

This work has received support from the Innovative Medicines Initiatives 2 Joint Undertaking (grant No 853989)

  1. WHO. Tuberculosis. https://www.who.int/news-room/fact-sheets/detail/tuberculosis.
  2. Palomino J, Martin A. Drug Resistance Mechanisms in Mycobacterium tuberculosis. Antibiotics. 2014;3(3):317-340. doi:10.3390/antibiotics3030317
  3. Kilinç, G., Saris, A., Ottenhoff, T. H. M., & Haks, M. C. (2021). Host-directed therapy to combat mycobacterial infections*. Immunological Reviews, 301(1), 62–83. https://doi.org/10.1111/imr.12951
  4. Cleverley, T. L., Peddineni, S., Guarner, J., Cingolani, F., Garcia, P. K., Koehler, H., Mocarski, E. S., & Kalman, D. (2023). The host-directed therapeutic imatinib mesylate accelerates immune responses to Mycobacterium marinum infection and limits pathology associated with granulomas. PLOS Pathogens, 19(5), e1011387. https://doi.org/10.1371/journal.ppat.1011387
  5. Hölscher, C., Gräb, J., Hölscher, A., Müller, A. L., Schäfer, S. C., & Rybniker, J. (2020). Chemical p38 MAP kinase inhibition constrains tissue inflammation and improves antibiotic activity in Mycobacterium tuberculosis-infected mice. Scientific Reports, 10(1), 13629. https://doi.org/10.1038/s41598-020-70184-x
  6. Clarke, W. A., Chatelut, E., Fotoohi, A. K., Larson, R. A., Martin, J. H., Mathijssen, R. H. J., & Salamone, S. J. (2021). Therapeutic drug monitoring in oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology consensus guidelines for imatinib therapy. European Journal of Cancer, 157, 428–440. https://doi.org/10.1016/j.ejca.2021.08.033
  7. Xia, Y., Chen, S., Luo, M., Wu, J., Cai, S., He, Y., Chen, X., & Zhang, X. (2020). Correlations between imatinib plasma trough concentration and adverse reactions in Chinese patients with gastrointestinal stromal tumors. Cancer, 126(S9), 2054–2061. https://doi.org/10.1002/cncr.32751
  8. Chien, Y.-H., Würthwein, G., Zubiaur, P., Posocco, B., Pena, M. Á., Borobia, A. M., Gagno, S., Abad-Santos, F., & Hempel, G. (2022). Population pharmacokinetic modelling of imatinib in healthy subjects receiving a single dose of 400 mg. Cancer Chemotherapy and Pharmacology, 90(2), 125–136. https://doi.org/10.1007/s00280-022-04454-y
  9. Wood, C. C., Yong, C.-L., Madwed, J. B., & Gupta, A. (2002). Safety, pharmacokinetics and pharmacodynamics of an oral p38 MAP kinase inhibitor (BIRB 796 BS), administered once daily for 7 days. Journal of Allergy and Clinical Immunology, 109(1), S321–S321. https://doi.org/10.1016/S0091-6749(02)82128-5
  10. Polmar, S., Yong, C.-L., Wood, C. C., Staehle, H., & Gupta, A. (2002). Safety and pharmacokinetics of an oral p38 MAP kinase inhibitor (BIRB 796 BS), administered twice daily for 14 days to healthy volunteers. Journal of Allergy and Clinical Immunology, 109(1), S66–S66. https://doi.org/10.1016/S0091-6749(02)81293-3
  11. W. Chanput, J. J. Mes, and H. J. Wichers, “THP-1 cell line: An in vitro cell model for immune modulation approach,” International Immunopharmacology, vol. 23, no. 1. Elsevier, pp. 37–45, 2014. doi: 10.1016/j.intimp.2014.08.002.

Reference: PAGE 32 (2024) Abstr 11063 [www.page-meeting.org/?abstract=11063]

Poster: Methodology - Other topics