Open AccessPharmacokinetic Evaluation of the Penetration of Antituberculosis Agents in Rabbit Pulmonary Lesions
Author(s) -
Maria C. Kjellsson,
Laura E. Via,
Anne Goh,
Danielle M. Weiner,
Kang Min Low,
Steven Kern,
Goonaseelan Pillai,
Clifton E. Barry,
Véronique Dartois
Publication year - 2012
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.05208-11
Subject(s) - pyrazinamide , moxifloxacin , pharmacokinetics , tuberculosis , isoniazid , medicine , mycobacterium tuberculosis , lung , pharmacology , pharmacodynamics , drug , lesion , population , antibiotics , antibacterial agent , cycloserine , pathology , biology , microbiology and biotechnology , environmental health
Standard antituberculosis (anti-TB) therapy requires the use of multiple drugs for a minimum of 6 months, with variable outcomes that are influenced by a number of microbiological, pathological, and clinical factors. This is despite the availability of antibiotics that have good activity againstMycobacterium tuberculosis in vitro and favorable pharmacokinetic profiles in plasma. However, little is known about the distribution of widely used antituberculous agents in the pulmonary lesions where the pathogen resides. The rabbit model of TB infection was used to explore the hypothesis that standard drugs have various abilities to penetrate lung tissue and lesions and that adequate drug levels are not consistently reached at the site of infection. Using noncompartmental and population pharmacokinetic approaches, we modeled the rate and extent of distribution of isoniazid, rifampin, pyrazinamide, and moxifloxacin in rabbit lung and lesions. Moxifloxacin reproducibly showed favorable partitioning into lung and granulomas, while the exposure of isoniazid, rifampin, and pyrazinamide in lesions was markedly lower than in plasma. The extent of penetration in lung and lesions followed different trends for each drug. All four agents distributed rapidly from plasma to tissue with equilibration half-lives of less than 1 min to an hour. The models adequately described the plasma concentrations and reasonably captured actual lesion concentrations. Though further refinement is needed to accurately predict the behavior of these drugs in human subjects, our results enable the integration of lesion-specific pharmacokinetic-pharmacodynamic (PK-PD) indices in clinical trial simulations and inin vitro PK-PD studies withM. tuberculosis .