A Once-Weekly R207910-containing Regimen Exceeds Activity of the Standard Daily Regimen in Murine Tuberculosis

216

132

2One-third of the world population is infected with Mycobacterium tuberculosis (MTB) and hence at risk of developing active tuberculosis (TB). Each year, 8.8 million patients are newly diagnosed with active TB and 1.6 million patients die of TB. The rapid spread of the human immunodeficiency virus (HIV) has fueled the TB epidemic, especially in sub-Saharan Africa, where 28% of TB patients are HIV positive (176). The current first-line treatment for TB is a multidrug regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE). It must be taken for at least 6 months to achieve high cure rates (more than 95% in experimental settings). PROBLEMS WITH CURRENT TUBERCULOSIS TREATMENTThere are several major problems associated with the currently available TB treatment. First, the duration and complexity of treatment result in nonadherence to treatment. This leads to suboptimal response (failure and relapse), the emergence of resistance, and continuous spread of the disease (168). Second, adverse events in response to anti-TB drugs are common and contribute to the problem of nonadherence (19,168). Third, the increasing incidence of multidrug-resistant (MDR; resistance to at least rifampin and isoniazid) and extensively drug-resistant (XDR; MDR resistance plus resistance to a fluoroquinolone and an aminoglycoside) TB is a serious concern. Resistant TB occurs in the presence of partially suppressive drug concentrations that enable replication of bacteria, the formation of mutants, and overgrowth of wild-type strains by mutants (selective pressure) (175). The prevalence of MDR TB in new TB cases ranged from 0% in some Western European countries to more than 22% in Azerbaijan (2002 to 2007 survey); 14 of 72 participating countries reported an MDR TB prevalence of more than 5% (177). Second-line drugs for drug-resistant TB are not available everywhere and are less effective, more toxic, and require longer use than first-line drugs (61). Fourth, coinfection of TB and HIV is a problem by itself. Combined treatment of TB and HIV involves a high pill count with associated adherence problems, overlapping toxicity profiles of the antiretroviral and anti-TB drugs, drug interactions between rifampin and the antiretroviral protease inhibitors, and the risk of immune reconstitution syndrome (104). Fifth, prophylactic therapy of latent TB (TB infection without symptoms) with isoniazid is also associated with problems of nonadherence (180). Attempts to shorten treatment with alternative drugs resulted in severe adverse events (64,150,155).The World Health Organization (WHO) has developed the directly observed therapy short course (DOTS) strategy to optimize response and adherence to TB treatment. However, DOTS is labor-intensive and expensive. It causes a high burden on public health programs, especially in developing countries with limited human resources (49). In addition, TB diagnosis in the DOTS strategy is based on sputum microscopy, rather than sputum culture (173). Only advanced pulmonary TB is detected by sputum...

Section: Ii) Gatifloxacin (A) Mechanism Of Actionmentioning

confidence: 83%

New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development

Boogaard

Kibiki

Kisanga

et al. 2009

216

132

“…Studies using multiple animal models have shown that bedaquiline is efficacious against M. tuberculosis, Mycobacterium leprae, and to some extent M. avium (25,(35)(36)(37). Bedaquiline potently inhibits the mycobacterial enzyme complex ATP synthase, thus interfering with energy production and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Mycobacterium abscessus to Antimycobacterial Drugs in Preclinical Models

Obregón-Henao

Arnett

Henao-Tamayo

et al. 2015

Self Cite

103

144

bOver the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.

“…In the murine model of tuberculosis, daily administration of TMC207 monotherapy during 4 weeks exceeded the bactericidal activity of the standard WHO regimen, which combines rifampin, isoniazid, and pyrazinamide (2). The efficacy of once weekly administration of TMC207 was similar to that of daily (5 days per week) administration (18). TMC207 synergized with pyrazinamide (7), and addition of TMC207 to first-or second-line drug regimens led to accelerated clearance of bacilli (2,12).…”

mentioning

confidence: 94%

Pharmacokinetics and Pharmacodynamics of TMC207 and Its N -Desmethyl Metabolite in a Murine Model of Tuberculosis

Rouan¹,

Lounis²,

Gevers³

et al. 2012

Self Cite

105

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.