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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis
Antimicrobial Agents and Chemotherapy, Volume 52, No. 8, Year 2008
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Description
Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naive patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log10 decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log10 CFU counts (± standard deviation) from baseline to day 7 were 0.04 ± 0.46 for 25 mg TMC207 (n = 14), 0.26 ± 0.64 for 100 mg TMC207 (n = 14), 0.77 ± 0.58 for 400 mg TMC207 (n = 14), 1.88 ± 0.74 for INH (n = 11), and 1.70 ± 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Authors & Co-Authors
Rustomjee, Roxana
South Africa, Tygerberg
South African Medical Research Council
Diacon, Andreas Henri
South Africa, Stellenbosch
Stellenbosch University
Allen, Jenny
South Africa, Tygerberg
South African Medical Research Council
Venter, Amour
South Africa, Stellenbosch
Stellenbosch University
Reddy, Carl
South Africa, Tygerberg
South African Medical Research Council
Patientia, R. F.
South Africa, Bellville
Karl Bremer Hospital
Mthiyane, Thuli C.P.
South Africa, Tygerberg
South African Medical Research Council
De Marez, T.
United States, Philadelphia
Tibotec Inc.
van Heeswijk, Rolf P.G.
Belgium, Mechelen
Virco Bvba
Kerstens, René
Belgium, Mechelen
Virco Bvba
Koul, A.
Belgium, Mechelen
Virco Bvba
De Beule, K.
Belgium, Mechelen
Virco Bvba
Donald, Peter Roderick
South Africa, Cape Town
Stellenbosch University, Faculty of Medicine and Health Sciences
McNeeley, D. F.
United States, Philadelphia
Tibotec Inc.
Statistics
Citations: 264
Authors: 14
Affiliations: 6
Identifiers
Doi:
10.1128/AAC.01204-07
ISSN:
00664804
Research Areas
Health System And Policy