Case Study: Famciclovir: A Prodrug of Penciclovir

Abstract

Famciclovir was designed as an orally bioavailable prodrug of penciclovir, an antiviral agent with activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) (Boyd et al., 1987; 1988). Penciclovir similarly to other guanosine analogs (De Miranda and Good, 1992; De Miranda et al., 1981), is poorly absorbed when given orally to rodents and humans (Boyd et al., 1988; Filer et al., 1994). Initially, various mono and dicarboxylic esters of penciclovir were made (Harnden et al., 1987), but none of these compounds resulted in significantly improved plasma concentration, of penciclovir when administered orally (Harnden et al., 1989). The physicochemical properties of penciclovir are, furthermore, influenced by the polar guanine ring, and it was thought that modifications on that ring might lead to improved absorption. The 6-deoxy derivative was made, since it was known from previous work with acyclovir (Krenitsky et al., 1984) that it would be oxidized to form penciclovir. When esters of the 6-deoxy derivative were tested a significant increase in bioavailability was observed (Harnden et al., 1989). After further evaluation of the stability of the 6-deoxy esters (Harnden et al., 1989), the diacetyl derivative, famciclovir, was selected for further development due to its improved stability in human duodenal contents (Jarvest, 1994). For more details on the design of famciclovir the reader is referred to several recent reviews (Jarvest, 1994; Jarvest et al., 1998).