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.
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