TB R&D Weekly Update: PA-824 Exhibits Time-Dependent Activity in Mice

Ahmad Z, Peloquin CA, Singh RP, Derendorf H, Tyagi S, Ginsberg A, Grosset JH, Nuermberger EL. PA-824 exhibits time-dependent activity in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011 Jan;55(1):239-45. Epub 2010 Oct 11.PMID: 20937781 [PubMed – in process]

Researchers testing the nitroimidazole PA-824 in phase II trials in humans observed early bactericidal activity (EBA) with doses ranging from 200 to 1200 mg per day, but did not observe any dose-response effect meaning there was no change in EBA with change in dose. In an article published in the January issue of Antimicrobial Agents and Chemotherapy, Ahmad, et al. presents preclinical data on PA-824 showing that its time dependent activity may shed light on why there is a lack of a dose-response effect of PA-824 in humans whereas there was a definite dose-response relationship observed in early studies in the murine model.

A dose-fractionation study was conducted with the following scheme:

Key Points from the article:

  • Pharmacodynamic (PD) studies like the one conducted should be utilized more in TB drug development to help with the selection of compounds and doses for preclinical studies and for the selection of dose for clinical trials.
  • For the PD of PA-824, the results indicate that free drug T>MIC [time the concentration of an antibiotic remains above the minimal inhibitory concentration (MIC)] correlates best with bactericidal activity.
  • The target values for T>MIC needed for near-maximal bactericidal effects can be achieved in humans with the daily doses of PA-824 that have been safely tested in phase I trials.
  • As explanation of the lack of dose-response effect seen in the EBA trial, PA-284 has a longer half-life in humans so near-maximal bactericidal effects were reached in all dose groups (200 to 1200 mg per day). The researchers surmise that a dose-response relationship would be seen at doses below 200 mg per day, but there would also be a reduction in bactericidal activity.

Other Interesting News in TB R&D:

TB Research Centre Set Up In Sabah Through Tri-party Collaboration

Pills with a mind of their own

FDA Launches website for food, drug companies in effort to improve accesibility [actual FDA link]

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