Specialized Anti-HIV Testing: Expediting Preclinical Drug Development
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0092-8615/97 Copyright 0 1997 Drug Information Association Inc.
SPECIALIZED ANTI-HIV TESTING: EXPEDITING PRECLINICAL DRUG DEVELOPMENT ROBERTW. BUCKHEIT, JR., PHD Manager, Virology Research Group, Southern Research Institute-Frederick Research Center, Frederick, Maryland
The ultimate goal of a preclinical development program for a potential anti-HIV agent must be to rapidly define the efficacy and toxicity of the candidate compound, as well as its range and mechanism of antiviral action, its activity in combination with other known anti-HIV drugs, and the relative rate at which it selects drug-resistant virus isolates. With this information, appropriate in vivo studies may be designed to further evaluate efficacy, drug metabolism, pharmacokinetics, and toxicity. In the absence of a well-defined animal model to evaluate anti-HIV efficacy in vivo, in vitro studies are of critical importance to the selection and prioritization of compounds for expedited development. A research and development program consisting of both cell-based and biochemical mechanism-based assays will be described which allows the rapid accumulation of data regarding the anti-HIV activity of a candidate compound required to judiciously select a compound likely to be effective in a clinical setting. This preclinical development program has been designed to address points to consider suggested by the Food and Drug Administration for new anti-HIV agents and to direct critical time and resources to the development of appropriate compounds. Key Words: Efficacy; Toxicity; Range of action; Mechanism of action; Preclinical evalua-
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INTRODUCTION
similar agents in development. It will also allow the selection of a drug candidate based on its novel mechanism of action, potency, or therapeutic utility in terms of combination anti-HIV activity and/or relative rate at which it selects for resistant virus isolates. In light of the cost and time associated with the development of an antiviral compound, expeditious definition of the basic biological and biochemical antiviral properties of the candidate compound must be of high priority. The ideal anti-HIV compound should yield long-term inhibition of HIV replication in all infected target cells and tissues and should be orally bioavailable and available in quantity at low cost. It should not readily result in the selection of drug-resistant virus
THE INITIAL STEPS IN the drug discovery process are critical to the development of an antiviral agent. Selection of the appropriate model for anti-HIV evaluation and the rapid and accurate quantitation of the efficacy and toxicity characteristics of the candidate compound will ensure that the compound can be comparatively evaluated relative to other
Based upon a presentation made at the DIA 31st Annual Meeting, June 25-29, 1995, Orlando, Florida. Reprint address: Dr. Robert W. Buckheit, Jr., Virology Research Group, Southern Research Institute-Frederick Research Center, 431 Aviation Way, Frederick, MD 21701.
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