1. New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response
- Author
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Bartelink, IH, Zhang, N, Keizer, RJ, Strydom, N, Converse, PJ, Dooley, KE, Nuermberger, EL, and Savic, RM
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Infectious Diseases ,Tuberculosis ,Orphan Drug ,Clinical Research ,Clinical Trials and Supportive Activities ,HIV/AIDS ,Rare Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Animals ,Antitubercular Agents ,Clinical Trials as Topic ,Drug Therapy ,Combination ,Humans ,Mice ,Inbred BALB C ,Mice ,Nude ,Mice ,SCID ,Models ,Theoretical ,Mycobacterium tuberculosis ,Time Factors ,Translational Research ,Biomedical ,Treatment Outcome ,Cardiorespiratory Medicine and Haematology ,Other Medical and Health Sciences ,General Clinical Medicine ,Cardiovascular medicine and haematology ,Pharmacology and pharmaceutical sciences - 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.
- Published
- 2017