Nonclinical pharmacokinetics and relative efficacy of the first 25 novel tuberculosis drug combinations from the PAN-TB consortium: Use of the BALB/c relapsing mouse model and combination pharmacokinetics within a modeling-based framework

Sordello, S.; Tagliavini, A.; Boulenc, X.; Brock, L.; Zannoni, S.; Roversi, C.; Visentin, R.; Metcalf, D.; Frederico, D.; Modolo, S.; Calusi, G.; Petterlini, R.; Golovkine, G.; Pascal, C.; Huc Claustre, E.; Vahlas, Z.; Pergher, M.; Mdluli, K.; Levi, M.; black, t.; Bates, R. H.; Wille, D. R.; Liu, Y.; Hayashi, Y.; Aguilar-Perez, C.; Hermann, D. J.; Hanna, D.; Upton, A.

doi:10.64898/2026.05.05.722941

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bioRxiv · 10.64898/2026.05.05.722941

Nonclinical pharmacokinetics and relative efficacy of the first 25 novel tuberculosis drug combinations from the PAN-TB consortium: Use of the BALB/c relapsing mouse model and combination pharmacokinetics within a modeling-based framework

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Abstract

The Project to Accelerate New Treatments for Tuberculosis (PAN-TB) aims to accelerate development of shorter, simpler and safer pan-TB combinations, effective for use in both Drug Susceptible (DS)- and Drug Resistant (DR)- TB patients. Towards this aim, bactericidal and sterilizing activity of 25 priority 4-drug combinations was evaluated at doses targeting clinically relevant exposures, in the BALB/c relapsing mouse model of TB. The combinations comprised 8 PAN-TB drugs and candidates: bedaquiline (B), pretomanid (Pa), delamanid (Del), quabodepistat (Q), sutezolid (Sut), GSK2556286 (286), GSK3211830 (830) and ganfeborole (GSK3036656, (656)). Combination PK studies in infected mice enabled dose selection and a population-PK approach guided dosing so that compounds should achieve mean AUC0-24 within 2-fold of their clinical target exposures during the efficacy studies. All test combinations showed time-dependent bactericidal activity, with six regimens reducing lung bacterial burdens below the limit of detection with 8 weeks treatment, similar to the comparator BPaMZ (M is moxifloxacin and Z as pyrazinamide). Cure/Relapse data were modelled to derive population time to cure 90% mice (T90) values. Fifteen PAN-TB combinations had T90s of less than 5 months, sterilizing mice faster than the standard of care for drug susceptible TB, RHZE/RH. The best-performing PAN-TB combinations, BPa830Sut, BPa286Sut and BQSut286, cured 90% of mice in less than 3 months. These 3 top-ranked 4-drug combinations are all centered on a diarylquinoline (B)/oxazolidinone (Sut) core, together with the nitroimidazole (Pa) or a DprE1 inhibitor (Q) plus a novel agent such as the LeuRS inhibitor (830) or the Rv1625c agonist (286).

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Sordello, S., Tagliavini, A., Boulenc, X., Brock, L., Zannoni, S., Roversi, C., Visentin, R., Metcalf, D., Frederico, D., Modolo, S., Calusi, G., Petterlini, R., Golovkine, G., Pascal, C., Huc Claustre, E., Vahlas, Z., Pergher, M., Mdluli, K., Levi, M., black, t., Bates, R. H., Wille, D. R., Liu, Y., Hayashi, Y., Aguilar-Perez, C., Hermann, D. J., Hanna, D., Upton, A.. 2026-05-07. Nonclinical pharmacokinetics and relative efficacy of the first 25 novel tuberculosis drug combinations from the PAN-TB consortium: Use of the BALB/c relapsing mouse model and combination pharmacokinetics within a modeling-based framework. https://doi.org/10.64898/2026.05.05.722941

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