Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model.
New drugs are needed to shorten the duration of tuberculosis treatment. R207910, a diarylquinoline, is very active against Mycobacterium tuberculosis both in vitro and in mice. In healthy volunteers, the coadministration of R207910 and rifampin induced the increased metabolism of R207910, resulting in a 50% reduction in the level of R207910 exposure. We assessed the impact of reducing the dose of R207910 on its efficacy when R207910 was combined with a background regimen of isoniazid, rifampin, and pyrazinamide. Addition of 25 mg/kg of body weight or 12.5 mg/kg R207910 to the background regimen resulted in faster bacterial clearance and culture negativity. The difference in efficacy between the two doses was not statistically significant. The minimal bactericidal dose of R207910 when it was tested as part of the combination was identical to that when it was tested as monotherapy. Because of the drug-drug interaction in humans, the activity of R207910 in humans could be less than that expected from studies with mice. Our data from the mouse model demonstrate that R207910 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of isoniazid, rifampin, and pyrazinamide. In killing kinetic studies, the bactericidal effect of R207910 in mice was modest during the first week of treatment, but it increased in the following 3 weeks, while the bactericidal activity of isoniazid was limited to the first week of treatment.
Lounis
Nacer
N
Department of Antimicrobial Research, Tibotec BVBA, Johnson & Johnson, Turnhoutseweg 30, Beerse 2340, Belgium. nlounis@tibbe.jnj.com
Gevers
Tom
T
Van Den Berg
Joke
J
Andries
Koen
K
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage; D000995:Antitubercular Agents / Q000008:administration & dosage*; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage*; D012293:Rifampin / Q000008:administration & dosage*; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; D011718:Pyrazinamide; C493870:bedaquiline; D007538:Isoniazid; D012293:Rifampin