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Advancing the development of new tuberculosis treatment regimens: The essential role of translational and clinical pharmacology and microbiology
Application of clinical pharmacology best practices is essential to the efficient and rational development of drugs. In general, knowledge gained about exposure–response relationships in preclinical models aids drug and dose selection in human studies, and biomarkers and pharmacokinetic (PK) data one collects in early to middle drug development can be used to predict the dose and treatment response of promising therapeutics in definitive phase 3 trials. The essentiality of sound clinical pharmacology in tuberculosis (TB) drug and regimen development is heightened by unique challenges in assessing drugs for this disease—aspects of the organism’s biology, the variability in lung pathology, uncertainties about how to link treatment outcomes seen in preclinical models with those seen in humans (which thwarts preclinical–clinical translational work), the lack of predictive early clinical biomarkers, and the high variability in treatment response across patients and populations (Fig 1). In TB disease, Mycobacterium tuberculosis (M.tb) bacilli are detected in necrotic granulomas, large cavities with liquefied contents, and intracellularly within macrophages. We believe that drugs must access each of these compartments to achieve cure in patients. We also believe that TB drugs and regimens must kill bacilli in different metabolic states, from actively multiplying to semidormant.
Dooley KE, Hanna D, Mave V, Eisenach K, Savic R (2019) Advancing the development of new tuberculosis treatment regimens: The essential role of translational and clinical pharmacology and microbiology. PLoS Med 16(7): e1002842. https:// doi.org/10.1371/journal.pmed.1002842