TY - JOUR
T1 - Nonclinical Models for Antituberculosis Drug Development
T2 - A Landscape Analysis
AU - Gumbo, Tawanda
AU - Lenaerts, Anne J.
AU - Hanna, Debra
AU - Romero, Klaus
AU - Nuermberger, Eric
N1 - Publisher Copyright:
© 2015 The Author.
PY - 2015/6/15
Y1 - 2015/6/15
N2 - 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.
AB - 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.
KW - Guinea pig tuberculosis model
KW - antituberculosis
KW - drug development
KW - drug regimen design
KW - hollow fiber system model of tuberculosis
KW - mouse tuberculosis model
UR - http://www.scopus.com/inward/record.url?scp=84937458786&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937458786&partnerID=8YFLogxK
U2 - 10.1093/infdis/jiv183
DO - 10.1093/infdis/jiv183
M3 - Article
C2 - 26009617
AN - SCOPUS:84937458786
SN - 0022-1899
VL - 211
SP - S83-S95
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
ER -