In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 56, No. 3 ( 2012-03), p. 1444-1451
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.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.00720-11
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2012
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
Bookmarklink