title: 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.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX Department of Medicine, University of Cape Town, South Africa.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer-Bazaga
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents
keywords: Monte Carlo simulations; antituberculosis agents; clinical correlations; dose identification; drug development; guinea pig model; hollow fiber system; mouse model; pharmacokinetics/pharmacodynamics; susceptibility breakpoint