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.Tuberculosis (TB) has reemerged as one of the most deadly infectious diseases worldwide, killing approximately 1.7 million people in 2004 (25). In Africa, more than 30% of new adult TB cases are coinfected with human immunodeficiency virus (HIV) (5). Widespread efforts to control the resurgence of TB, such as the implementation of outcome-driven treatment programs (16) and the introduction of "directly observed therapy short-course" (26), have had limited success, in part due to constrained public health resources and the length of treatment needed to sterilize infectious TB lesions. The global situation is deteriorating further with the spread of multidrugresistant (MDR) TB (7, 8) and, more recently, extensively drug-resistant TB (9). There is an urgent need for new anti-TB agents that can shorten treatment duration and are effective in treating drug-sensitive, drug-resistant, and latent TB infection (22).Tibotec Medicinal Compound 207 (TMC207) (also known as R207910) belongs to a newly identified chemical class with antimycobacterial properties. TMC207 demonstrates unique and specific antimycobacterial activity by inhibiting the oligomeric and proteolipic subunit c of mycobacterial ATP synthase, a critical enzyme in the synthesis of ATP (17). Binding of TMC207 to subunit c leads to inhibition of ATP synthesis, which subsequently results in bacterial death. In vitro mycobacterial susceptibility experimen...

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