Pharmacologic considerations in use and development of antituberculosis drugs

Abstract

Rational development and deployment of antituberculosis drugs depend on a comprehensive understanding of the pharmacokinetics and pharmacodynamics that underlie their clinical behavior. Successful implementation of a pharmacokinetic-pharmacodynamic approach faces difficulties that, although not unique to tuberculosis as a therapeutic area, in combination pose a significant scientific challenge. In recent years, a multidisciplinary response combining new technological and analytical approaches has begun to directly address many of these issues, shedding light on some previously poorly understood aspects of drug distribution and response. These advances have important implications for optimization of existing and development of novel drug regimens, putting quantitative pharmacology at the heart of preclinical and early drug development.

Figure 1.

Components of pharmacokinetic–pharmacodynamic models. Determinants of drug action include pharmacokinetics (systemic absorption [K_a] and elimination [K_e] of drug distribution of a biophase [K_d]) and pharmacodynamics (direct binding to or inhibition or stimulation of production [K_in] or removal [K_out] of a mediator biosignal, and transduction of the response). (Modified from Jusko et al. 1995.)

Figure 2.

Simplified scheme of a transition pharmacodynamic model for tuberculosis treatment. Boxes represent the size of subpopulations with arrows representing possible transitions between them. Each subpopulation has a defined death rate, which has been omitted for clarity, with the exception of the viable but nonculturable population at the bottom of the figure. As therapy proceeds, subpopulations are sequentially eliminated according to their characteristics.