Screening for potential toxicity of antiviral therapies

Preclinical screening for the toxicity of antiviral drugs has thus far proven quite successful. Twenty-three antivirals spanning a variety of chemical classes and including a combination product, have been safely developed and are listed in the 1999 Physician's Desk Reference. Several of these antivirals have been administered for many years and in various combinations and we are currently unaware of any being withdrawn for safety-related reasons. Progress in protecting this record includes advances in rational drug design, the development of in vitro and in vivo models available to study both efficacy and safety, and improved bioanalytical capabilities. Coupled with approximately 25 years of experience since vidarabine was approved for the treatment of herpes encephalitis, these advances set the stage for even more precise and focused development of pharmaceuticals for the treatment of life-threatening viral infections, including those caused by HIV, HBV and emerging viruses. Experience to date suggests that each antiviral, particularly the nucleoside analogs, may have unique attributes of efficacy and safety. This brief review is an attempt to highlight a combination of established and recent methods that may be helpful in screening antivirals for potential toxicity. The earliest phases of drug development are mentioned in the introduction, followed by contributions provided by in vitro and in vivo testing in models of viral disease. Finally, current and new methods applicable to screening for toxicity are discussed.