Early bactericidal activity and pharmacokinetics of the diarylquinoline TMC207 in treatment of pulmonary tuberculosis

Abstract

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.

Figures

FIG. 1.

Study flow diagram. Eight patients did not complete the treatment phase. Five patients were withdrawn due to screening laboratory values that emerged only after randomization (five with a positive urine drug screen for cannabinoids and one with elevated liver enzymes). Two individuals in the INH group were withdrawn following hemoptysis. Two patients died during follow-up (for details, see the text).

FIG. 2.

Bactericidal activities for days 0 to 7 by treatment regimen. The activities of 300 mg isonazid and 600 mg rifampin are of immediate onset and continuous over 7 days. TMC207 shows delayed onset of activity from day 4. The values are means. Log Fall, change in log10 CFU/ml sputum from baseline to day 7. The error bars are 95% confidence intervals.

FIG. 3.

Decline in CFU from baseline to day 7 for individual subjects by treatment group. Log Fall, change in log10 CFU/ml sputum from baseline to day 7.