Acyclovir Information

Description:
Acyclovir is an oral, parenteral, and topical antiviral agent. Chemically, it is a synthetic purine nucleoside analog. Its antiviral spectrum is limited to herpes viruses including herpes simplex, herpes zoster, Epstein-Barr virus, and cytomegalovirus. Acyclovir is not active against the human immunodeficiency virus. Clinically, use of acyclovir is limited to the treatment of herpes simplex, herpes genitalis, and herpes zoster infections. Acyclovir was approved by the FDA in March 1982 and comes off patent in 1997. It is marketed in oral, parenteral, and topical formulations. The FDA is planning to review a request to market an OTC form of acyclovir in January 1995. An acyclovir ester is currently under investigation.

Mechanism of Action:
 Acyclovir must be phosphorylated to be active. Intracellularly, acyclovir is converted to the monophosphate by viral thymidine kinases, then to diphosphate by cellular guanylate kinase, and finally to the triphosphate by various cellular enzymes. Fully active acyclovir triphosphate competes with the natural substrate, deoxyguanosine triphosphate, for a position in the DNA chain of the herpes virus. Once incorporated, it terminates DNA synthesis. Uninfected cells show only minimal phosphorylation of acyclovir, and there is only a small amount of uptake into these cells. It is believed that mutations in the viral thymidine kinase or polymerase genes lead to acyclovir resistance.ææñ Acyclovir is effective only against actively replicating viruses; it does not eliminate the latent herpes virus genome.

Although resistance to acyclovir does occur, it appears the infectivity of resistant strains is less than that of other strains. Loss of thymidine kinase activity is the most common cause of resistance, although a decrease in DNA-polymerase sensitivity or impaired acyclovir phosphorylation can also contribute to resistance. Acyclovir resistance by herpes simplex virus has gradually progressed from in vitro and animal models to immunocompromised patients, and recently it has been seen in patients with HIV infection and immunocompetent patients with genital herpes. The development of viral mutants can occur in immunosuppressed patients who receive repeated systemic treatment. During an infection, the virus leaves the site of infection and invades other cells establishing a latent site of infection, often within the ganglia. The mechanism during this stage is not fully understood, but the virus is believed to be in a dormant state and therefore not susceptible to acyclovir. Latency lasts for life, and the virus can be reactivated and can reinfect the initial site of infection.

Pharmacokinetics:
 Following topical application, there is minimal percutaneous absorption, and no drug is detected in the blood or urine. Following oral administration, acyclovir is poorly absorbed from the GI tract; bioavailability is roughly 20%. (An amino acid ester form of acyclovir - valaciclovir - with increased bioavailability is currently under investigation.) Food has little affect on absorption. Peak serum concentrations occur in about 1.5 to 2 hours. Acyclovir distributes extensively, with the highest concentrations in the kidneys, liver, and intestines. CSF concentrations are about 50% of plasma, and acyclovir crosses the placenta. Protein binding is 9 to 33%.

Acyclovir is minimally metabolized. Infected viral cells transform acyclovir to its active triphosphate, and a small proportion may be metabolized extracellularly. Roughly 70% of circulating drug is eliminated unchanged in the urine. Due to poor oral bioavailability, only about 14% of the total dose can be recovered in the urine, compared with about 92% after systemic administration.