PA-824 exhibits time-dependent activity in a murine model of tuberculosis

Zahoor Ahmad, Charles A. Peloquin, Rajendra P. Singh, Hartmut Derendorf, Sandeep Tyagi, Ann Ginsberg, Jacques H. Grosset, Eric L. Nuermberger

Research output: Contribution to journalArticle

Abstract

PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T>MIC (R2 = 0.87) and correlated with the free drug AUC/MIC (R2 = 0.60), but not with the free drug Cmax/MIC (R2 = 0.17), where T>MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of ≤72 h, both the T>MIC and the AUC/MIC values fit the data well. Free drug T>MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T >MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T>MIC, in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.

Original languageEnglish (US)
Pages (from-to)239-245
Number of pages7
JournalAntimicrobial agents and chemotherapy
Volume55
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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  • Cite this

    Ahmad, Z., Peloquin, C. A., Singh, R. P., Derendorf, H., Tyagi, S., Ginsberg, A., Grosset, J. H., & Nuermberger, E. L. (2011). PA-824 exhibits time-dependent activity in a murine model of tuberculosis. Antimicrobial agents and chemotherapy, 55(1), 239-245. https://doi.org/10.1128/AAC.00849-10