PHARMACOLOGICAL CONSIDERATIONS FOR ANTIVIRAL DRUG DEVELOPMENT

OBJECTIVE: TO discuss pharmacologic considerations for the development of antiviral agents. DATA SOURCES: English-language literature pertai ning to the development and clinical evaluation of antiviral compounds , primarily agents targeted against herpes group viruses and HIV. STUD Y SELECTION AND DATA EXTRACTION: Pertinent information, as judged by t he author, was selected for discussion. DATA SYNTHESIS: Drug developme nt of antiviral agents presents unique problems compared with that of antimicrobial and other agents. Understanding the mechanism of action and both pharmacokinetic and pharmacodynamic considerations is critica l to developing a rational dosing strategy and safe, effective use. Th e lack of standardized methods for antiviral susceptibility testing an d the influence of factors such as strain of virus, host cell type, cu lture medium, inoculum size, end point and method of measurement on th e results obtained illustrate factors that complicate preclinical phar macologic analysis of antiviral agents. Acyclovir offers a model for c linical drug development. Its mechanism of action, pharmacokinetics, a nd pharmacodynamics have been studied extensively, Rational guidelines for usage are available, including guidelines in special patient popu lations such as kidney transplant recipients and neonates. A pregnancy registry has allowed evaluation of the incidence of birth defects in fetuses exposed to systemic acyclovir. Several pitfalls in antiviral d rug development are associated with inadequate pharmacologic informati on. The development of dextran sulfate and fialuridine provides two ex amples, Integration of pharmacokinetic and pharmacodynamic analyses us ing modem sampling and analysis techniques may facilitate more rapid d evelopment of antiviral agents and more informed dosage regimens to ac hieve the highest probability of therapeutic success. CONCLUSIONS: Ins ufficient knowledge of the pharmacokinetic and pharmacodynamic charact eristics of an antiviral agent is a barrier to efficient drug developm ent. Application and early integration of pharmacologic information in to clinical investigations hold promise as a means to shorten the deve lopment process and, more importantly, to arrive at informative dosing regimens that optimize therapeutic success.