TB R&D Weekly Update: Recommended Dose of Pyrazinamide Could Be Inadequate

Chemical Structure of Pyrazinamide

Ahmad Z, Fraig MM, Bisson GP, Nuermberger EL, Grosset JH, Karakousis PC. Dose-dependent activity of pyrazinamide in animal models of intracellular and extracellular tuberculosis. Antimicrob Agents Chemother. 2011 Jan 31. [Epub ahead of print]

First discovered as an agent against TB in 1952, pyrazinamide has confounded scientist for decades. It was found in the 1980’s to have a synergistic effect when included in a treatment regimen with isoniazid and rifampin enabling treatment for TB to be shortened from 9 months to 6 months, but PZA’s mechanism of action remains elusive. Based on published data from in vitro pharmakinetic studies, Ahmad, et al., investigate in mice and guinea pigs whether higher doses of PZA may improve treatment outcomes in TB patients. The authors emphasize three key findings from their experiments:

  1. In contrast to studies published in the early 1950’s indicating that PZA was not active in guinea pigs, the drug was highly active in the chronic TB guinea pig model. At a dose of 300 mg/kg, granulomas in the guinea pig were reduced in number and size.
  2. PZA given at recommended human doses exhibits similar activity in mice and guinea pigs. In both animal models, increasing doses of PZA resulted in greater degree of bactericidal activity. Doses below the recommended human dose had little or no bactericidal activity, while the recommended doses had significant activity.
  3. When the recommended human doses were doubled, the resulting activity increased substantially. Doubling PZA in the mouse model from 150 mg/kg to 300 mg/kg reduced the bacilli in the lung from 1.0 log10 to 1.7 log10 at the higher dose (p=0.003). In the guinea pig, doubling the dose from 300 mg/kg to 600 mg/kg reduced the bacilli in the lung from 1.1 log10 to 3.0 log10.

The authors conclude that a higher dose of PZA in the standard regimen may lead to better treatment outcomes in TB patients and would like to see this investigated in clinical trials. A paper published last year in AAC by Dr. Tawanda Gumbo provided data suggesting that doubling the current dose may not result in higher risk of hepatotoxicity in humans.

Additional R&D News:

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Nigeria: Multi-Drug Resistant TB Epidemic Imminent in Country

REVIEW: The challenge of new drug discovery for tuberculosis

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