Title
A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
New York ,
Subject
Pharmacology. Therapy
Source (journal)
American journal of respiratory and critical care medicine. - New York, 1994, currens
Volume/pages
179(2009) :1 , p. 75-79
ISSN
1073-449X
1535-4970
ISI
000262050900013
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Rationale: R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis. Objectives: To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide). Methods: The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs. Measurements and Main Results: Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log10 for rifapentine and by 5 to 6 log10 for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week. Conclusions: The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.
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