Impact of the Interaction of R207910 with Rifampin on the Treatment of Tuberculosis Studied in the Mouse Model

Abstract

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.New antituberculosis (anti-TB) drugs that have the potential to shorten the current duration of therapy for both active and latent tuberculosis and to improve the efficacy of treatment regimens for multidrug-resistant (MDR) TB are urgently needed.R207910 (TMC207), a diarylquinoline, is a new compound that exhibits a new mode of action (inhibition of ATP synthase) against mycobacteria (1, 6). The compound is being assessed in a phase IIb trial for the treatment of active tuberculosis in patients with MDR-TB. In vitro, R207910 is active against sensitive and resistant strains of Mycobacterium tuberculosis (1, 2). In mice, it accelerates bacterial clearance when it is combined with regimens active against both sensitive and MDR Mycobacterium tuberculosis (1, 10), Mycobacterium leprae (4), and Mycobacterium ulcerans (5).In the established murine model of tuberculosis, monotherapy with R207910 is as active as the standard WHO regimen, which combines rifampin (RIF), isoniazid (INH), and pyrazinamide (PZA); and when it was combined with RIF-INH-PZA (RHZ), INH-PZA, or RIF-PZA, the lungs of mice became culture negative after just 2 months of treatment (1).When R207910 is combined with PZA, R207910 acts synergistically in the murine model (3). In fact, after only 2 months of treatment, the combination of R207910 and PZA led to the complete eradication of the 7.2 log 10 CFU that was present in the lungs of mice at the onset of treatment. Such a level of efficacy needed 4 months of treatment with the triple-drug combination RIF-moxifloxacin-PZA (11).An ext...

Development of New Anti-tuberculosis Drug Candidates

“…Addition of 25 mg/kg of body weight or 12.5 mg/kg TMC207 to the background regimen resulted in faster bacterial clearance and culture negativity. The difference in efficacy between the two doses was not statistically significant (Lounis et al 2008). The minimum bactericidal dose of TMC207 when it was tested as part of the combination was identical to that when it was tested as monotherapy.…”

“…The area under the concentration-time curve (AUC) from time zero to 336 h for TMC207 after its coadministration with RIF was about half that of when it was administered alone, indicating that metabolism of TMC207 is induced by coadministration with RIF (Rustomjee et al 2008b). Lounis et al (Lounis et al 2008) assessed the impact of reducing the dose of TMC207 on its efficiency when TMC207 was combined with a background regimen of INH, RIF and PZA. Addition of 25 mg/kg of body weight or 12.5 mg/kg TMC207 to the background regimen resulted in faster bacterial clearance and culture negativity.…”

“…Because of drug-drug interaction in humans, the activity of TMC207 might be less than that expected from studies with mice. Data from the mouse model demonstrate that TMC207 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of INH, RFP, and PZA (Lounis et al 2008). In killing kinetic studies, the bactericidal effect of TMC207 in mice was modest during the first week of treatment, but increased in the following 3 weeks, while the bactericidal activity of isoniazid was limited to the first week of treatment (Lounis et al 2008).…”

A New Hope in TB Treatment: The Development of the Newest Drugs

“…The area under the concentration-time curve (AUC) from time zero to 336 h for TMC207 after its coadministration with RIF was about half that when it was dosed alone, indicating that the metabolism of TMC207 is induced by coadministration with RIF. Lounis et al (Lounis et al, 2008) assessed the impact of reducing the dose of TMC207 on its efficiency when TMC207 was combined with a background regimen of INH, RIF and PZA. Addition of 25mg/kg of body weight or 12.5mg/kg TMC207 to the background regimen resulted in faster bacterial clearance and culture negativity.…”

“…Because of the drug-drug interaction in human, the activity of TMC207 in human could be less than that expected from studies with mice. Data from the mouse model demonstrate that TMC207 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of INH, RFP, and PZA (Lounis et al, 2008). In killing kinetic studies, the bactericidal effect of TMC207 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.…”