Population Pharmacokinetics and its Role in Anti-Tuberculosis Drug Development and Optimization of Treatment

Eric      Free Egelund; Aline      Bergesch Barth; Charles      Arthur Peloquin

Abstract

Tuberculosis (TB) has survived for millennia due to its unique physiochemical properties and its ability to persist in a “dormant” state. Because of these unique properties, the treatment of TB involves multiple drugs for half of a year or longer. Although the incidence of TB has declined in most developing countries, it remains poorly controlled in much of the developing world. This is partly driven by co-infection with HIV in these settings. Concern about this dual epidemic has renewed interest in anti-tuberculosis drugs, and this in turn has led to increasing amounts of pharmacokinetic data regarding TB drugs.

Population pharmacokinetics has proven useful for many disease states, providing a valuable tool with which to explore data and predict future events. It not only generates pharmacokinetic parameter estimates, but it includes patient characteristics (covariates) that may alter those parameters. We review the population pharmacokinetic studies undertaken with anti-TB medications. In addition to the primary medications used in TB treatment (rifampin, isoniazid, pyrazinamide, and ethambutol) we discuss the fluoroquinolones, various software packages, and the covariates that were found to be significant in each study.

Keywords: Population pharmacokinetics, rifampin, rifabutin, rifapentine, pyrazinamide, ethambutol, fluoroquinolones, epithelial lining fluid (ELF), alveolar cell concentrations, monotherapy