Ganciclovir and Valganciclovir

Mechanism of Action. Ganciclovir, like acyclovir, inhibits viral DNA replication by inhibiting DNA polymerase activity and by halting elongation of viral DNA chains. 

Adverse Effects. The most serious problems associated with ganciclovir include anemia, granulocytopenia, thrombocytopenia, and related hematologic disorders. Ganciclovir may also cause gastrointestinal disturbances (nausea, loss of appetite) and CNS disturbances (mood changes, nervousness, tremor). 

Antiviral Efficacy and Clinical Use. Imiquimod (Aldara) is applied topically to treat condylomata acuminate infections that cause genital and perianal warts.42 It can also be used to treat certain skin conditions such as actinic keratoses of the face and scalp. 

Mechanism of Action. Although the details are unclear, imiquimod enhances the local production of interferons, tumour necrosis factor-alpha, and possibly other cytokines that produce antiviral responses. Hence, this drug does not act directly on the virus, but instead modulates the host (human) immune responses that have antiviral effects. 

Adverse Effects. Some local skin irritation and blistering can occur when imiquimod is applied topically. 

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Buffering agents that are compounded with didanosine to counteract its degradation by gastric acid may interfere with the absorption of other drugs that require acidity (e.g., indinavir, delavirdine, ketoconazole, fluoroquinolones, tetracyclines, dapsone). An enteric-coated formulation Videx EC) that dissolves in the basic pH of the small intestine is not susceptible to these interactions. Ganciclovir and valganciclovir can increase blood levels of didanosine. The use of zalcitabine with didanosine is not recommended because that combination carries an additive risk of peripheral neuropathy. The combination of didanosine with stavudine increases the risk of pancreatitis, hepatotoxicity, and peripheral neuropa-... 

Absorption - Valganciclovir is well absorbed from the Gl tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. The absolute bioavailability of ganciclovir from valganciclovir tablets following administration with food was about 60%. Ganciclovir median administration of... 

Lactation It is not known whether ganciclovir or valganciclovir is excreted in human milk. Because of potential for serious adverse events in nursing infants, mothers should be instructed not to breastfeed if they are receiving valganciclovir tablets. In addition, the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. 

Drugs eliminated by the kidneys Coadministration of tenofovir with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir. Drugs that decrease renal function also may increase serum concentrations of tenofovir. 

Keven K, Basu A, Tan HP, Thai N, Khan A, Marcos A, Starzl TE, Shapiro R. Cytomegalovirus prophylaxis using oral ganciclovir or valganciclovir in kidney and pancreas-kidney transplantation under antibody preconditioning. Transplant Proc 2004 36(10) 3107-12. 

Intravenous ganciclovir, oral ganciclovir, and oral valganciclovir reduce the risk of CMV disease in solid-organ transplant recipients. Oral ganciclovir (1000 mg three times daily for 3 months) reduces CMV disease risk in liver... 

TRIMETHOPRIM GANCICLOVIR/ VALGANCICLOVIR Possibly t adverse effects (e.g, myelosuppression) when trimethoprim is co administered with ganciclovir or valganciclovir Small t in bioavailability possible additive toxicity Well tolerated in a study. For patients at risk of additive toxicities, use only if benefits outweigh risks, and monitor FBC closely... 

Probenecid reduces the renal excretion and increases the plasma levels of aciclovir, valaciclovir, and ganciclovir. Famciclovir and valganciclovir are predicted to interact similarly. 

Based on an early possible report, the manufacturer notes that generalised seizures have been reported in patients who received ganciclovir with imipenem-cilastatin. They recommend that ganciclovir and its prodrug valganciclovir should not be used with imipenem unless the benefits outweigh the risks.No further reports of this interaction appear to have been published, or reported to the manufacturer. Note that both ganciclovir and imipenem alone may cause seizures. 

Sugawara, M., et al. Transport of valganciclovir, a ganciclovir prodrug, via peptide transporters PEPT1 and PEPT2. /. Pharm. Sci. 2000, 89, 781-789. 

The clinical toxicity of valganciclovir, which is metabolized to ganciclovir, includes granulocytopenia, anemia, and thrombocytopenia. In animal studies, ganciclovir was carcinogenic, teratogenic, and caused aspermatogenesis. 

Pharmacology Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of 2 diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. 

Excretion - The major route of elimination of valganciclovir is by renal excretion as ganciclovir through glomerular filtration and active tubular secretion. Systemic clearance of IV administered ganciclovir was about 3.07 mL/min (n = 68) while renal clearance was about 2.99 mL/min/kg (n = 16). 

The terminal half-life of ganciclovir following oral administration of valganciclovir tablets to either healthy or HIV-positive/CMV-positive subjects was about 4.08 hours (n = 73), and that following administration of IV ganciclovir was about 3.81 hours (n = 69). 

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, bone marrow depression, and aplastic anemia have been observed in patients treated with valganciclovir tablets (and ganciclovir) (see Precautions and Adverse Reactions). 

Drug/Food interactions When valganciclovir tablets were administered with a high-fat meal containing about 600 total calories (31.1 g fat, 51.6 g carbohydrates, and 22.2 g protein) at a dose of 875 mg once daily to 16 HIV-positive subjects, the steady-state ganciclovir AUC increased by 30% (95% Cl 12% to 51%), and the Cmax... 

Oral valganciclovir is comparable to intravenous ganciclovir for the treatment and suppression of CMV retinitis in AIDS patients. 

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