Nonclinical Models for Antituberculosis Drug Development: A Landscape Analysis

Tawanda Gumbo, Anne J. Lenaerts, Debra Hanna, Klaus Romero, Eric Nuermberger

Research output: Contribution to journalArticle

Abstract

Background Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug development over several decades. The role of the DDTs used for evaluating the efficacy of antituberculosis drug combinations and the gaps in the evidence base for which new tools or approaches are needed are as yet undefined. Methods We performed a landscape analysis based on a comprehensive literature review to create evidence based guidelines. Results There are 3 important questions that a DDT should answer with regard to antituberculosis drugs: What combination(s) of drugs will be most effective? What dose(s) and schedule(s) of each drug should be administered? and What duration(s) of treatment will be efficacious? Four DDTs were identified as having a track record to answer these questions: in vitro susceptibility tests, the hollow fiber system model of tuberculosis, mice, and Guinea pigs. No single nonclinical in vitro or animal model recapitulates all aspects of human tuberculosis. Therefore, a combination of models is recommended for drug development. Gaps identified include the need for standardization of nonclinical model experiments, evaluation of animal models with pathology more similar to that in humans, and identification of experimental quantitative output in the DDTs that correlates with sterilizing effect in humans. Conclusions There is a need for formal quantitative analyses of how well DDTs forecast clinical outcomes.

Original languageEnglish (US)
Pages (from-to)S83-S95
JournalJournal of Infectious Diseases
Volume211
DOIs
StatePublished - Jun 15 2015

Keywords

  • Guinea pig tuberculosis model
  • antituberculosis
  • drug development
  • drug regimen design
  • hollow fiber system model of tuberculosis
  • mouse tuberculosis model

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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