@article{472d0dfda32a4fea80b96dc134289762,
title = "New Paradigm for Translational Modeling to Predict Long-term Tuberculosis Treatment Response",
abstract = "Disappointing results of recent tuberculosis chemotherapy trials suggest that knowledge gained from preclinical investigations was not utilized to maximal effect. A mouse-to-human translational pharmacokinetics (PKs) – pharmacodynamics (PDs) model built on a rich mouse database may improve clinical trial outcome predictions. The model included Mycobacterium tuberculosis growth function in mice, adaptive immune response effect on bacterial growth, relationships among moxifloxacin, rifapentine, and rifampin concentrations accelerating bacterial death, clinical PK data, species-specific protein binding, drug-drug interactions, and patient-specific pathology. Simulations of recent trials testing 4-month regimens predicted 65% (95% confidence interval [CI], 55–74) relapse-free patients vs. 80% observed in the REMox-TB trial, and 79% (95% CI, 72–87) vs. 82% observed in the Rifaquin trial. Simulation of 6-month regimens predicted 97% (95% CI, 93–99) vs. 92% and 95% observed in 2RHZE/4RH control arms, and 100% predicted and observed in the 35 mg/kg rifampin arm of PanACEA MAMS. These results suggest that the model can inform regimen optimization and predict outcomes of ongoing trials.",
author = "Bartelink, {I. H.} and N. Zhang and Keizer, {R. J.} and N. Strydom and Converse, {P. J.} and Dooley, {K. E.} and Nuermberger, {E. L.} and Savic, {R. M.}",
note = "Funding Information: The authors thank the Critical Path to TB Drug Regimens (CPTR) and specifically the advice and support of the M&S team at CPTR. In addition, we thank the researchers in the Center for Tuberculosis Research at The Johns Hopkins University School of Medicine who conducted the mouse model experiments that generated the data used in these analyses: Deepak Almeida, Opokua Amoabeng, Fabrice Betoudji, Jean-Philippe Lanoix, Si-Yang Li, Austin Minkowski, Aimee Ormond, Sang Won Park, Zahoor Parry, Ian Rosenthal, Rokeya Tasneen, Dinesh Taylor, Sandeep Tyagi, Kathy Williams, Tetsuyuki Yoshimatsu, Ming Zhang, and Tianyu Zhang. This work was supported by the National Institutes of Health (R01AI111992) and by the Critical Path to TB Drug Regimens initiative which is a funded through the Bill & Melinda Gates Foundation (OPP1031105). The mouse efficacy data used for the analyses were generated with support from the National Institutes of Health, the U.S. Food and Drug Administration, the Bill & Melinda Gates Foundation, and the Global Alliance for TB Drug Development. Dr Zhang was supported by the Clinical Pharmacology Postdoctoral Fellowship at JHU. Dr Bartelink received funding from the Ruth L. Kirschstein National Research Service Award T32 National Institutes of Health grant, 5T32GM007546. I.H.B., N.Z., R.J.K., N.S.S., P.J.C., K.E.D., E.L.N., and R.M.S. wrote the manuscript. I.H.B., N.Z., R.J.K., P.J.C., K.E.D., E.L.N., and R.M.S. designed the research. I.H.B., N.Z., R.J.K., N.S.S., E.L.N., and R.M.S. performed the research. I.H.B., N.Z., R.J.K., N.S.S., K.E.D., and R.M.S. analyzed the data. I.H.B., N.Z., E.L.N., and R.M.S. contributed new reagents/analytical tools. Publisher Copyright: {\textcopyright} 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2017",
month = sep,
doi = "10.1111/cts.12472",
language = "English",
volume = "10",
pages = "366--379",
journal = "Cts-clinical and translational science",
issn = "1752-8054",
publisher = "Wiley-Blackwell",
number = "5",
}