Relative contributions of the novel diarylquinoline TBAJ-876 and its active metabolite to the bactericidal activity in a murine model of tuberculosis.
J Infect Dis
; 2024 Jun 28.
Article
em En
| MEDLINE
| ID: mdl-38941358
ABSTRACT
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. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model.METHODS:
In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M. tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3-exposure following TBAJ-876 treatment and corresponding M3-activity observed in M3-treated animals.RESULTS:
TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture-negative. Following TBAJ-876 treatment, M3-exposures were 2.2-3.6x higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity.CONCLUSION:
These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
J Infect Dis
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Holanda