Translational pharmacology: from animal to man and backBridging the gap in the fight against tuberculosis
Introduction
Limited scientific understanding of Mycobacterium tuberculosis and the disease that it causes has been a major obstacle to the development of improved tools for tuberculosis control. Nowhere has this been more true than in the field of drug development. Unresolved questions in the basic biology and pharmacology of tuberculosis introduce uncertainty and risk into all phases of development of anti-tuberculosis drugs from discovery right through to completion of pivotal trials. Since only a single novel agent has been licensed for this indication in the last thirty years, the critical path to effective development of new anti-tuberculosis is currently poorly defined and remains a significant source of controversy in the field, with sometimes disturbing disconnects between preclinical expectations and performance in clinical trials (Fig. 1).
A central problem concerns the extent to which in vitro and in vivo systems capture the pharmacodynamics of anti-tuberculosis treatment in humans. In order to ensure stable cure in tuberculosis, treatment must be prolonged for at least six months with at least three drugs in order to prevent the emergence of resistance. Despite substantial reductions in the load of organisms in clinical specimens in the early weeks of therapy, the surviving ‘persister’ organisms, often beyond the reach of detection of current diagnostic or monitoring methods, remain capable of causing recrudescent disease should treatment be stopped prematurely. Understanding the biological nature and vulnerabilities of these organisms is the key to overcoming the limitations of existing therapy.
Recent research has generated new insights into the most important features of the persister state. Such organisms in vivo either cease growth completely or have an extremely prolonged generation time [1]. A wide range of conditions in vitro induce qualitatively similar changes in gene regulation and expression associated with adaptation to stationary phase in a hostile environment [2]. Energy metabolism undergoes profound changes with a switch in preferred carbon-source to beta-oxidation of free fatty acids [3] and accumulation of intracellular triacyl glycerol droplets [4]. Transpeptidation in the mycobacterial cell wall adopts a different pattern of linkages in the absence of growth [5]. Most importantly of all the altered metabolic state is associated with phenotypic tolerance to many classes of existing antimicrobials characterised by altered pharmacodynamics or complete absence of lethal effect [6].
The existence of these organisms is a major difficulty in clinical development because endpoints in clinical trials are based on bacteriological methods that reflect only the subpopulation of organisms that remain capable of growth. These measures are also insensitive and provide little information after the first two months of therapy. Hence, definitive evidence of efficacy relies on demonstrating relapse after therapy is stopped often requiring many hundreds of patients in a Phase III trial. Development of new preclinical systems that more accurately reflect the persister state is currently a key goal for preclinical scientists, while clinical developers would similarly benefit from better methods of identifying and quantifying such organisms in clinical specimens. We review here recent advances in this area and reflect on how they could be harnessed in an integrated approach to drug development in tuberculosis.
Section snippets
In vitro systems
While convenient, traditional screening methods using logarithmic phase organisms at a relatively low inoculum with exposure to static drug concentrations and expression of pharmacodynamic outcome at a single, fixed timepoint has serious limitations for M tuberculosis. Some important anti-tuberculosis drugs completely lack activity in this context depending on assay conditions such as pH and carbon source in the medium [7]. Assays based only on inhibition of growth and not lethality may be
Conclusions
Current problems in drug development for tuberculosis reflect an incomplete understanding of the pharmacodynamics of combination drug regimens in vivo. The legacy of thirty years of inactivity in the field is a poorly defined development pathway which relies heavily on empirically selected surrogate endpoints from a narrow set of historical agents. New experimental techniques are beginning to have an impact on these obstacles both in the preclinical and clinical phases of development. In vitro
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Cited by (1)
The implications of model-informed drug discovery and development for tuberculosis
2017, Drug Discovery TodayCitation Excerpt :An overview of current recommendations for the implementation of a model-informed approach as envisaged by PreDiCT-TB is presented in Table 1. TB has seen many exciting advances in preclinical research [18,19]. The availability of preclinical models that reflect key human pathological features of TB infection would be a valuable tool for translating PKPD concepts, offering a strong rationale for clinical trial designs [20,21].