Effective dose, therapeutic index, and drug toxicity

Because of the intimate replication of viruses within cells, and their absolute reliance on cellular protein and energy metabolisms, the development of antiviral compounds faces the difficult challenge of selective toxicity – interference with viral replication needs to

Figure:  The various stages of virus replication. Antiviral drugs can be used to inhibit any of these steps.

be achieved without unacceptable damage to the  host  (uninfected cells). The activity of antiviral compounds is assessed at an early stage in their development, quantifying their ability to interfere with viral growth in tissue culture. The replication of the target virus is assayed by, for example, TCID50 or plaque assay, comparing levels of infection within cells  in  the  presence of various concentrations of the  drug  candidate (with  drug-free

Figure   Chemical structures of guanosine and  aciclovir, revealing the  exchange of a single hydroxyl (OH) group for hydrogen (H) within the  ribose sugar  ring.

control infections alongside). The resulting level of virus infectivity is plotted against the drug concentration and the concentration of compound that reduces virus titer by 50% is expressed as the effective dose 50 concentration (ED₅₀); if achievable, the ED₉₀ concentration is also determined. Tissue culture can also be used to assess the toxicity.

       Figure:  Determination of effective dose (ED50, ED90) for an antiviral drug in tissue culture.

of compounds, although this is often tested in animals and  humans. Animals play a vital role in the study of toxicity  and  a number of statutory tests  are carried out to determine the  risks  and  side  effects  before new  compounds enter clinical trials.  Drug  toxicity  is expressed as the selective index,  which determines the ratio  between the concentration at which the drug inhibits cell proliferation or DNA synthesis (i.e. it is toxic to uninfected cells),  and  the  concentration at which the  drug  inhibits virus  replication. A high value indicates a selective drug with low toxicity, while a ratio approaching equivalence indicates that the compound is toxic. For compounds with a less than ideal selective index, a consideration of benefit/risk ratio can be appropriate, as side effects may be tolerated more if the risk from the disease is high (e.g. AIDS). Some antiviral agents have a level of toxicity which, while acceptable for some diseases (e.g. AIDS), would not be tolerated for less severe diseases.