| Indication |
For induction and maintenance in the treatment of cytomegalovirus
(CMV) retinitis in immunocompromised patients, including patients with
acquired immunodeficiency syndrome (AIDS). Also used in the treatment of
severe cytomegalovirus (CMV) disease, including CMV pneumonia, CMV
gastrointestinal disease, and disseminated CMV infections, in
immunocompromised patients. |
| Pharmacodynamics |
Ganciclovir is a synthetic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.
Sensitive human viruses include cytomegalovirus (CMV), herpes simplex
virus -1 and -2 (HSV-1, HSV-2), Epstein-Barr virus (EBV) and varicella
zoster virus (VZV), however clinical studies have been limited to
assessment of efficacy in patients with CMV infection. Ganciclovir is a
prodrug that is structurally similar to acyclovir. It inhibits virus
replication by its encorporation into viral DNA. This encorporation
inhibits dATP and leads to defective DNA, ceasing or retarding the viral
machinery required to spread the virus to other cells. |
| Mechanism of action |
Ganciclovir's antiviral activity inhibits virus replication. This
inhibitory action is highly selective as the drug must be converted to
the active form by a virus-encoded cellular enzyme, thymidine kinase
(TK). TK catalyzes phosphorylation of ganciclovir to the monophosphate,
which is then subsequently converted into the diphosphate by cellular
guanylate kinase and into the triphosphate by a number of cellular
enzymes. In vitro, ganciclovir triphosphate stops replication of
herpes viral DNA. When used as a substrate for viral DNA polymerase,
ganciclovir triphosphate competitively inhibits dATP leading to the
formation of 'faulty' DNA. This is where ganciclovir triphosphate is
incorporated into the DNA strand replacing many of the adenosine bases.
This results in the prevention of DNA synthesis, as phosphodiester
bridges can longer to be built, destabilizing the strand. Ganciclovir
inhibits viral DNA polymerases more effectively than it does cellular
polymerase, and chain elongation resumes when ganciclovir is removed. |
| Absorption |
Poorly absorbed systemically following oral administration.
Bioavailability under fasting conditions is approximately 5%, and when
administered with food, 6 to 9% (about 30% with a fatty meal). |
| Volume of distribution |
|
| Protein binding |
1 to 2% |
| Metabolism |
Little to no metabolism, about 90% of plasma ganciclovir is eliminated unchanged in the urine. |
| Route of elimination |
Renal excretion of unchanged drug by glomerular filtration and
active tubular secretion is the major route of elimination of
ganciclovir. |
| Half life |
2.5 to 3.6 hours (mean 2.9 hours) when administered intravenously
in adults. 3.1 to 5.5 hours when administered orally in adults. Renal
function impairment causes a marked increase in half life (9 to 30 hours
intravenously, 15.7 to 18.2 hours orally). |
| Clearance |
- 128 +/- 63 mL/min [Patients with Renal Impairment (Clcr=50-79 mL/min)]
- 57+/- 8 mL/min [Patients with Renal Impairment (Clcr=25-49 mL/min)]
- 30 +/- 13 mL/min [Patients with Renal Impairment (Clcr<25 mL/min)]
- 4.7+/- 2.2 mL/min/kg [pediatric patients, aged 9 months to 12 years]
|
| Toxicity |
Oral, mouse LD50: > 2g/kg. Intravenous, dog LD50:
> 150mg/kg. Symptoms of overdose include irreversible pancytopenia,
worsening GI symptoms, and acute renal failure. Suspected cancer agent. |
