Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients

Diacon, Andreas H.; Dawson, Rodney; Hanekom, Madeleine; Narunsky, Kim; Maritz, Stefan J.; Venter, Amour; Donald, Peter R.; Niekerk, Christo van; Whitney, Karl; Rouse, Doris; Laurenzi, Martino; Ginsberg, Ann M.; Spigelman, Melvin

doi:10.1128/aac.01354-09

Cited by 165 publications

(123 citation statements)

References 20 publications

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“…In the monotherapy trials, a daily dose of 50 mg had lower bactericidal activity than higher doses, but there was no significant difference in bactericidal activity of daily doses from 100 to 1200 mg. The NC-001 trial demonstrated excellent bactericidal activity in the PaMZ combination at a daily dose of 200 mg [77,78]. An 8-week phase IIb serial sputum colony counting trial demonstrated a greater time-dependent decline of viable bacteria in subjects with drug-sensitive pulmonary TB at 8 weeks (71.4% negative in liquid culture in comparison with only 37.8% of subjects treated with the standard HRZE control; p<0.05) [7].…”

Section: The Stand Trialmentioning

confidence: 99%

The role of moxifloxacin in tuberculosis therapy

Gillespie

2016

Eur Respir Rev

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Tuberculosis (TB) remains a global threat with more than 9 million new infections. Treatment remains difficult and there has been no change in the duration of the standard regimen since the early 1980s. Moreover, many patients are unable to tolerate this treatment and discontinue therapy, increasing the risk of resistance. There is a growing tide of multidrug resistance and few effective antibiotics to tackle the problem. Since the turn of the millennium there has been a surge in interest in developing new therapies for TB and a number of new drugs have been developed. In this review the repurposing of moxifloxacin, an 8-methoxy-fluoroquinolone, for TB treatment is discussed. The evidence that underpins the development of this agent is reviewed. The results of the recently completed phase III trials are summarised and the reasons for the unexpected outcome are explored. Finally, the design of new trials that incorporate moxifloxacin, and that address both susceptible disease and multidrug resistance, is described. @ERSpublications A review of the role of moxifloxacin in tuberculosis therapy http://ow.ly/WaAyC

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Section: The Stand Trialmentioning

confidence: 99%

The role of moxifloxacin in tuberculosis therapy

Gillespie

2016

Eur Respir Rev

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“…For tuberculosis, lack of a reliable biomarker of treatment response makes it difficult to define PK-PD relationships. PA-824 is being tested in a 2-month phase 2B treatment trial at doses of 100 mg and 200 mg daily because doses from 100 mg to 1,000 mg had similar activities in the 2-week dose-ranging phase 2A monotherapy studies; only at 50 mg daily was early bactericidal activity (EBA) decreased (33,34). Preclinical studies suggest time-dependent activity of PA-824 against M. tuberculosis (35), suggesting that the AUC 0 -24 may be a key pharmacodynamic parameter; however, target AUC values have not been defined.…”

Section: Discussionmentioning

confidence: 99%

Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

Dooley

Luetkemeyer

Park

et al. 2014

Antimicrob Agents Chemother

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“…In humans, PA-824 has been well tolerated with constant pharmacodynamic parameters when given once daily, with the maximum serum drug level reached about 4-5 h following oral administration [59,67,68].…”

Section: Pa-824 ( Pretomanid)mentioning

confidence: 99%

Novel drugs against tuberculosis: a clinician's perspective

et al. 2014

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The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens. @ERSpublications A review of the efficacy, safety, and potential of new drugs to improve TB therapy from the perspective of clinicians

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Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients

Cited by 165 publications

References 20 publications

The role of moxifloxacin in tuberculosis therapy

The role of moxifloxacin in tuberculosis therapy

Phase I Safety, Pharmacokinetics, and Pharmacogenetics Study of the Antituberculosis Drug PA-824 with Concomitant Lopinavir-Ritonavir, Efavirenz, or Rifampin

Novel drugs against tuberculosis: a clinician's perspective

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