Development and dose rationale for drug combinations for the treatment of tuberculosis

Better, short treatment options are urgently needed for tuberculosis (TB). To meet this need, drug development in TB requires the use of new integrated methods to ensure the transition of suitable drugs and drug combinations into clinical development, which may ultimately lead to shortening of treatment duration. Despite the ongoing evaluation of new agents in preclinical stages of research, the translation of drug effects to humans along with the corresponding regimens remains empirical, in that novel regimens are progressed without consideration of target exposure or the underlying pharmacokinetic-pharmacodynamic relationships. Hence, one of most critical questions in drug development regards the rationale for the selection of dose and drug combinations. In the first part of this investigation, pharmacokinetic properties of common antitubercular drugs in mice were characterized, followed by an assessment of the utility of plasma concentrations as surrogate for lung tissue exposure. In the second section, data arising from various in vivo experiments were integrated into a drug-disease modelling framework to assess the impact of differences in disease properties on treatment response and disentangle the effect ... (continues)