Antimicrob Agents Chemother
Global Alliance for TB Drug Development, New York, New York, USA.
Published: October 2024
TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin). TBAJ-876 was well-tolerated at single doses up to 800 mg and multiple doses up to 200 mg for 14 days. No deaths or serious adverse events occurred. No episodes of clinically significant prolongation of the QTc interval were observed. TBAJ-876 exposures were dose proportional in the SAD and MAD studies. TBAJ-876 exhibited multicompartmental pharmacokinetics (PK) with a long terminal half-life yielding quantifiable concentrations up to the longest follow-up of 10 weeks after a single dose and resulting in accumulation with multiple dosing. In the fed state, TBAJ-876 exposures approximately doubled with the tablet formulation, whereas M3 metabolite exposures decreased by approximately 20%. The relative bioavailability of TBAJ-876 was similar between tablets and the oral suspension at 100-mg doses. With co-administration of TBAJ-876, the AUC of midazolam was unchanged and the C was reduced by 14%; the AUC of digoxin was increased by 51%, and the C was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis.
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http://dx.doi.org/10.1128/aac.00613-24 | DOI Listing |
Biomed Environ Sci
November 2024
Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
Antimicrob Agents Chemother
October 2024
Global Alliance for TB Drug Development, New York, New York, USA.
TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). A phase 1, first-in-human study of TBAJ-876, comprising a single-ascending dose (SAD) part including a food effect cohort, a multiple-ascending dose (MAD) part, and a relative bioavailability part of tablets versus oral suspension, was conducted on 137 healthy adults. A drug-drug interaction study was conducted on 28 healthy adults to evaluate the effects of TBAJ-876 on a cytochrome P450 3A4 substrate (midazolam) and a P-glycoprotein substrate (digoxin).
View Article and Find Full Text PDFJ Infect Dis
December 2024
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, The Netherlands.
Background: TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-to-metabolite ratios might impact the translational value of animal model-based predictions.
View Article and Find Full Text PDFAntimicrob Agents Chemother
February 2024
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Multidrug-resistant (MDR) (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDTs) offer a novel approach to TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that the inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden when co-administered with the first-line antitubercular regimen.
View Article and Find Full Text PDFMicrobiol Spectr
December 2023
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!
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