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 log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of
TMC207 administration up to 24 h postdose. The decreases in log(10) 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.