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 halflives (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 g/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 g/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.

Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry

“…Bedaquiline drug concentrations at the end of treatment were higher than the values previously reported at week 8 (13). M2 values were low, as expected (3). No drug-drug interactions were expected as no CYP3A4 inhibitors were coadministered.…”

“…Since the antimicrobial action of bedaquiline is exposure dependent (2,3), it is necessary, as with any drug with exposuredependent killing characteristics, that target exposures are reached. Current data from animal studies on optimal drug exposure have not yet been translated to and validated in human studies.…”

“…This drug is indicated for treatment of multidrug-resistant pulmonary tuberculosis (MDR-TB) in combination with other active anti-TB drugs in adults without other treatment options (1). This new anti-TB drug, formally known as TMC207, showed exposure-dependent killing of Mycobacterium tuberculosis (2,3). The drug is metabolized by cytochrome P 450 enzyme 3A4 (CYP3A4) to its 5-foldless-active metabolite N-monodesmethyl bedaquiline (M2) (4).…”

Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis

“…Bedaquiline similarly accumulates to very high levels in the tissues in both people (30) and mice (31), and the accumulated drug in tissue homogenates results in carryover and growth inhibition of M. tuberculosis on non-charcoal-containing agar (23). Despite the extremely high tissue concentrations, bedaquiline is maintained at a relatively low and steady concentration in serum, which is thought to be due to steady release of the drug from the tissues (30); and it has also been suggested that it is the serum drug levels, rather than the tissue drug levels, that represent active drug (31).…”

Activities of Moxifloxacin in Combination with Macrolides against Clinical Isolates of Mycobacterium abscessus and Mycobacterium massiliense

“…To determine the effect of antibiotic interactions in macrophages and in mice, the antibiotic activity of the combination treatment was defined as the log 10 CFU reduction as previously reported with slight modifications (32,40). Briefly, the antimycobacterial activity was assessed by counting the CFU from the macrophage lysates or the homogenates of inoculated organs on 7H10 agar supplemented with 10% OADC and determining the log 10 CFU per ml after 5 days.…”