Famciclovir, from the bench to the patient--a comprehensive review of preclinical data.
Famciclovir is converted rapidly and efficiently after oral administration to the selective antiviral compound, penciclovir. In cell culture, penciclovir is a potent inhibitor of herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and hepatitis B virus (HBV). Phosphorylation of penciclovir and aciclovir in uninfected cells is limited, and penciclovir, like aciclovir, has minimal effect on replicating cells in culture as expected for a selective antiviral agent. Mode of action studies with VZV and HSV have shown that the phosphorylation of penciclovir in infected cells is far more efficient than for aciclovir. This compensates for differences observed between penciclovir triphosphate and aciclovir triphosphate in the inhibition of HSV and VZV DNA polymerases. Because HBV is not known to encode a thymidine kinase, a different rationale for the selective inhibition of this virus by penciclovir is required. Recent data indicate that the DNA polymerase of HBV is far more sensitive to inhibition by penciclovir triphosphate than cellular DNA polymerases, suggesting that for this virus, selectivity operates at the DNA polymerase. Penciclovir triphosphate is more stable within infected cells than aciclovir triphosphate, and consequently penciclovir has more prolonged antiviral activity than aciclovir. Similarly, famciclovir is more effective than aciclovir or valaciclovir in suppressing HSV replication when given at a lower dosing frequency in certain animal models. These preclinical properties have helped to provide the foundation for the famciclovir clinical programme.
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SimithKline Beecham Pharmaceuticals, New Frontiers Science Park (South), Third Avenue, Harlow, Essex CM19 5AW, UK.