Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis

Abstract

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.

Fig 1

Mean (n = 3) plasma concentrations of TMC207 and N-desmethyl TMC207 in Swiss mice following single oral administration (30 mg/kg) of TMC207.

Fig 2

Relationship between the mycobacterial counts in the lungs (expressed as log₁₀ CFU) versus N-desmethyl TMC207 plasma pharmacokinetic parameters C_max (A), AUC_168h (B), and C_min (C) in mice after oral administration of N-desmethyl TMC207 for 5 days per week at 8, 16, 32, and 64 mg/kg for 28 days. The open circles represent the individual experimental values, and the solid lines represent the model-derived relationship as determined using an inhibitory sigmoid E_max model.

Fig 3

Plot of mycobacterial counts in the lungs (expressed as log₁₀ CFU) versus N-desmethyl TMC207 plasma AUC_168h in mice after oral administration of TMC207 for 5 days per week at 6.25, 12.5, 25, and 50 mg/kg or N-desmethyl TMC207 for 5 days per week at 8, 16, 32, and 64 mg/kg for 28 days. The solid line represents the N-desmethyl TMC207 model-derived relationship determined using an inhibitory sigmoid E_max model following N-desmethyl TMC207 administration. The dotted line represents the fitting of the mycobacterial counts in the lungs and the desmethyl TMC207 plasma AUC_168h to an inhibitory sigmoid E_max model.

Fig 4

Relationship between the mycobacterial counts in the lungs (expressed as log₁₀ CFU) versus a TMC207 weekly dose in mice after oral administration of TMC207 given 5 days per week (5/7), twice weekly (2/7), or once weekly (1/7) for 6 weeks. The lines represent the fitting of the data to an inhibitory sigmoid E_max model.

Fig 5

Simulated steady-state 168-hour plasma profiles of TMC207 (A) and N-desmethyl TMC207 (B) assuming linear kinetics upon repeated administration of a total TMC207 weekly dose of 30 mg/kg given once weekly (30 mg/kg per administration) or 5 days per week (6 mg/kg per administration). conc, concentration.