Hepatitis C. Development of new drugs and clinical trials: Promises and pitfalls. Summary of an AASLD hepatitis single topic conference, Chicago, IL, February 27–March 1, 2003
✍ Scribed by Jean-Michel Pawlotsky; John G. McHutchison
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 298 KB
- Volume
- 39
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
hronic hepatitis C virus (HCV) infection affects a large number of patients worldwide. While our current therapies (Table ) are effective in approximately 50% of patients, therapy is costly, prolonged, and associated with significant side effects, and it is not suitable for certain groups of patients. For these reasons, improved treatment regimens are necessary for patients with this disease. In February 2003, the annual American Association for the Study of Liver Diseases (AASLD) Single Topic Conference devoted to viral hepatitis and to fostering development of research in this field focused on recent advances in the process of antiviral drug design and new anti-HCV drugs currently in development. The drug design process, how these agents should be evaluated in future clinical trials, the potential problems and pitfalls related to pharmacodynamics and pharmacokinetics, viral resistance, clinical trial end points and design, and drug interactions, as well as HCV targets for novel drug development and the HCV drug pipeline were discussed.
The preface and aims of the conference were to provide investigators with new knowledge and some of the necessary tools to aid in planning future rational clinical trial design in this rapidly changing field.
Preclinical Studies
New treatment for HCV requires the development of new agents with unique biological profiles that are effective against a broad range of viral genotypes. While drug or target discovery represents the beginning of the process, multiple additional studies are required before an antiviral agent becomes a clinically effective and safe drug. Using a modern systematic drug discovery and development process, the risk of failure in the clinic can be markedly reduced. In the case of small antiviral compounds, the process generally consists of the following steps (communication by R.F. Schinazi, Decatur, GA):
• The first step is the screening of already existing libraries of potential compounds or the design and synthesis of new molecules based on potential target site structure knowledge.
• It is then necessary to rapidly test the potency and toxicity of potential agents-i.e. the selectivity of the targets and actions.
• The stability of the chemical entity and protein binding must be evaluated under various conditions.
• The mechanisms of action of the compound must be explored with appropriate in vitro tools.
• Toxicology studies must be run in at least two animal species. If the toxicity profile is acceptable, then the compound joins the "hot list" of compounds to proceed.
• The metabolism of the compound must be understood, and pharmacokinetics studies must be performed in animals.
• Efficacy studies must be performed in animals.
• The ultimate preclinical steps include various studies testing drug combinations in vitro and in vivo, selection of resistant viruses, viral fitness, pyrophosphorolysis, and others.