TMC207 is a first-in-class
diarylquinoline with a new mode of action against mycobacteria targeting the
ATP synthase. It is metabolized to an active derivative, N-desmethyl
TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro,
TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl
TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of
tuberculosis (TB)
infection following
oral administration of different doses of
TMC207 or N-desmethyl
TMC207 at 5 days per week for 4 weeks starting the day after intravenous
infection with M.
tuberculosis and following administration of different doses of
TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after
infection. Upon administration of N-desmethyl
TMC207, maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC(168h)), and minimum plasma concentration (C(min)) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (E(max)) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log(10) reduction of the bacillary load at an average exposure (average concentration [C(avg)] or AUC(168h) divided by 168) of 2.7 μg/ml. Upon administration of the highest dose of
TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log(10).
TMC207 was estimated to contribute to a 1.8-log(10) reduction and its corresponding exposure (C(avg)) was 0.5 μg/ml. Optimal bactericidal activity with N-desmethyl
TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with
TMC207. Following administration of
TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC(168h)) to
TMC207 and N-desmethyl
TMC207 mirrored this dose response, indicating that the bactericidal activity of
TMC207 is concentration dependent and that AUC is the main PK-PD driver on which dose optimization should be based for dosing frequencies up to once weekly. The PK-PD profile supports intermittent administration of
TMC207, in agreement with its slow release from tissues.