Developing New Drugs for Mycobacterium tuberculosis Therapy: What Information Do We Get from Preclinical Animal...

Preclinical animal models of infection are employed to develop new agents but also to screen among molecules to rank them. There are often major differences between human pharmacokinetic (PK) profiles and those developed by animal models of infection, and these may lead to substantial differences in efficacy relative to that seen in humans. Linezolid is a repurposed agent employed to great effect for therapy of Mycobacterium tuberculosis In this study, we used the hollow-fiber infection model (HFIM) to evaluate the impact of different pharmacokinetic profiles of mice and nonhuman primates (NHP) versus humans on bacterial cell kill as well as resistance suppression. We examined both plasma and epithelial lining fluid (ELF) profiles. We examined simulated exposures equivalent to 600 mg and 900 mg daily of linezolid in humans. For both plasma and ELF exposures, the murine PK profile provided estimates of effect that were biased low relative to human and NHP PK profiles. Mathematical modeling identified a linkage between minimum concentrations (C_min) and bacterial kill and peak concentrations (C_peak) and resistance suppression, with the latter being supported by a prospective validation study. Finding new agents with novel mechanisms of action against M. tuberculosis is difficult. It would be a tragedy to discard a new agent because of a biased estimate of effect in a preclinical animal system. The HFIM provides a system to benchmark evaluation of new compounds in preclinical animal model systems against human PK effects (species scale-up estimates of PK), to safeguard against unwarranted rejection of promising new agents.