New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response

• Published in: Clinical and translational science Vol. 10; no. 5; pp. 366 - 379
• Main Authors: Bartelink, IH, Zhang, N, Keizer, RJ, Strydom, N, Converse, PJ, Dooley, KE, Nuermberger, EL, Savic, RM
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-09-2017; John Wiley and Sons Inc
• Subjects: Adaptive immunity; Animals; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; Chemotherapy; Clinical trials; Clinical Trials as Topic; Computer simulation; Disease; Drug dosages; Drug Therapy, Combination; Humans; Immune response; Infections; Mice, Inbred BALB C; Mice, Nude; Mice, SCID; Models, Theoretical; Moxifloxacin; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Optimization; Pathology; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Researchers; Rifampin; Studies; Time Factors; Translation; Translational Medical Research; Treatment Outcome; Tuberculosis; Tuberculosis - drug therapy
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.12472

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.