Impact of the interaction of R207910 with rifampicin on the treatment of murine tuberculosis
Abstract number: P1922
Lounis N., Gevers T., Van Den Berg J., Andries K.
Objectives: New drugs are needed to shorten the duration of TB treatment. R207910, a diarylquinoline, is very active against Mycobacterium tuberculosis both in vitro and in mice. In healthy volunteers, co-administration of rifampicin induces increased metabolism of R207910 and as a result, exposure to R207910 is decreased by 50%. A similar drug-drug interaction is not observed in mice, and the efficacy in mice may therefore overestimate the efficacy in patients. The aim of this study is to evaluate the impact of decreasing doses of R207910 when used in combination with isoniazid (H), rifampicin (R) and pyrazinamide (Z) on the efficacy in the mouse model.
Methods: Mice were infected intravenously with 107M. tuberculosis and were treated 2 weeks later with the combination of HRZ and R207910 given at 3, 6.25, 12.5 or 25 mg/kg for 2, 4, 6 and 8 weeks. The CFU counts in the spleens were measured and the proportion of mice having negative cultures were determined.
Results: When RHZ was combined with 25 mg/kg of J, all mice had culture negative spleens after 6 weeks of treatment. When RHZ was combined with 12.5 mg/kg of J, almost all mice had culture negative spleens after 8 weeks of treatment. When RHZ was combined with 6 mg/kg of J, 4 of 6 mice had culture negative spleens after 8 weeks of treatment R207910 given at 3 mg/kg did not improve the treatment of mice when combined with RHZ.
Conclusion: In mice, the dose of R207910 could be decreased from 25 to 12.5 mg/kg without loosing too much bactericidal efficacy. Neither the use of a strong background regimen (RHZ) nor the presence of rifampicin is expected to conceal the efficacy of R207910 in patients.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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