Pharmacokinetic-pharmacodynamic and dose-response relationships of antituberculosis drugs: recommendations and standards for industry and academia

Abstract

Background: Antimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science is vital to early antibiotic drug development to enable more efficient dose-effect study designs, identification of doses that may suppress drug resistance and choice of susceptibility breakpoints. Proper conduct of such studies is essential in the field of tuberculosis.

Methods: We conducted an exhaustive review of literature on the hollow fiber system (HFS) model, murine model, and guinea pig model of tuberculosis as well as clinical studies to identify PK/PD studies that have been applied to antituberculosis therapy. Lessons learned are presented as recommendations and standards for both industry and academia in the field of antituberculosis drug development.

Results: PK/PD studies have been performed for both first-line and experimental antituberculosis agents. When properly designed exposure-effect and dose-fractionation studies have been performed in preclinical models, optimal drug exposures, and PK/PD parameters identified in these models have been found to be similar to clinical studies. Susceptibility breakpoints identified using these methods differed from previous concentrations in the literature but were found to be similar to those in prospective clinical studies.

Conclusions: Preclinical PK/PD studies are essential value added in the development of antituberculosis agents. We provide 8 recommendations and standards for the proper conduct of such studies.

Keywords: Monte Carlo simulations; antituberculosis agents; clinical correlations; dose identification; drug development; guinea pig model; hollow fiber system; mouse model; pharmacokinetics/pharmacodynamics; susceptibility breakpoint.