Ganciclovir


Ganciclovir is an antiviral medication used to treat cytomegalovirus infections. A prodrug form with improved oral bioavailability has also been developed.
Ganciclovir was patented in 1980 and approved for medical use in 1988.

Medical use

Ganciclovir is indicated for:
It is also used for acute CMV colitis in HIV/AIDS and CMV pneumonitis in immunosuppressed patients.
Ganciclovir has also been used with some success in treating Human herpesvirus 6 infections.
Ganciclovir has also been found to be an effective treatment for herpes simplex virus epithelial keratitis.

Adverse effects

Ganciclovir is commonly associated with a range of serious haematological adverse effects. Common adverse drug reactions include: granulocytopenia, neutropenia, anaemia, thrombocytopenia, fever, nausea, vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, anorexia, raised liver enzymes, headache, confusion, hallucination, seizures, pain and phlebitis at injection site, sweating, rash, itch, increased serum creatinine and blood urea concentrations.

Toxicity

Ganciclovir is considered a potential human carcinogen, teratogen, and mutagen. It is also considered likely to cause inhibition of spermatogenesis. Thus, it is used judiciously and handled as a cytotoxic drug in the clinical setting.

Mechanism of action

Ganciclovir is a synthetic analogue of 2′-deoxy-guanosine. It is first phosphorylated to ganciclovir monophosphate by a viral kinase encoded by the cytomegalovirus gene UL97 during infection. Subsequently, cellular kinases catalyze the formation of ganciclovir diphosphate and ganciclovir triphosphate, which is present in 10-fold greater concentrations in CMV or herpes simplex virus -infected cells than uninfected cells.
Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. In addition, ganciclovir triphosphate serves as a poor substrate for chain elongation, thereby disrupting viral DNA synthesis by a second route.

Pharmacokinetics

Absorption of the oral form is very limited—about 5% fasting, about 8% with food. It achieves a concentration in the central nervous system of about 50% of the plasma level. About 90% of plasma ganciclovir is eliminated unchanged in the urine, with a half-life of 2–6 hours, depending on renal function.

Administration

Acute infections are treated in two phases:
Stable disease is treated with 1000 mg orally three times daily. Similar dosing is used to prevent disease in high-risk patients, such as those infected with human immunodeficiency virus or those with organ transplants.
Ganciclovir is also available in slow-release formulations for insertion into the vitreous humour of the eye, as treatment for CMV retinitis.
A topical ophthalmic gel preparation of ganciclovir was recently approved for the treatment of acute herpes simplex keratitis.