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Antimicrobial Agents and Chemotherapy, August 2008, p. 2831-2835, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.01204-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Early Bactericidal Activity and Pharmacokinetics of the Diarylquinoline TMC207 in Treatment of Pulmonary Tuberculosis

Unit for Clinical and Biomedical Tuberculosis Research, Medical Research Council, Durban, South Africa,¹ Centre for Clinical Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical TB Research,² Paediatrics and Child Health, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa,⁶ Tiervlei Trial Centre, Karl Bremer Hospital, Bellville, South Africa,³ Tibotec, Inc., Yardley, Pennsylvania,⁴ Tibotec, BVBA, Mechelen, Belgium⁵

Received 12 September 2007/ Returned for modification 20 November 2007/ Accepted 25 April 2008

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-naïve 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.

Published ahead of print on 27 May 2008.

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