Valcyte Online, Description, Chemistry, Ingredients - valganciclovir

Valcyte Online, Description, Chemistry, Ingredients - valganciclovir

DESCRIPTION

Valcyte (valganciclovir HCl tablets) contains valganciclovir hydrochloride (valganciclovir HCl), a hydrochloride salt of the L-valyl ester of ganciclovir that exists as a mixture of two diastereomers. Ganciclovir is a synthetic guanine derivative active against cytomegalovirus (CMV).

Valganciclovir is available as a 450 mg tablet for oral administration. Each tablet contains 496.3 mg of valganciclovir HCl (corresponding to 450 mg of valganciclovir), and the inactive ingredients microcrystalline cellulose, povidone K-30, crospovidone, and stearic acid. The film-coat applied to the tablets contains Opadry Pink®.

Valganciclovir HCl is a white to off-white crystalline powder with a molecular formula of C ₁₄ H ₂₂ N ₆ O ₅ ·HCl and a molecular weight of 390.83. The chemical name for valganciclovir HCl is L-Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9- yl)methoxy]-3-hydroxypropyl ester, monohydrochloride. Valganciclovir HCl is a polar hydrophilic compound with a solubility of 70 mg/mL in water at 25°C at a pH of 7.0 and an n-octanol/water partition coefficient of 0.0095 at pH 7.0. The pKa for valganciclovir is 7.6.

All doses in this insert are specified in terms of valganciclovir.

VIROLOGY

Mechanism of Action

Valganciclovir is an L-valyl ester (prodrug) of ganciclovir that exists as a mixture of two diastereomers. After oral administration, both diastereomers are rapidly converted to ganciclovir by intestinal and hepatic esterases. Ganciclovir is a synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human cytomegalovirus in vitro and in vivo.

In CMV-infected cells ganciclovir is initially phosphorylated to ganciclovir monophosphate by the viral protein kinase, pUL97. Further phosphorylation occurs by cellular kinases to produce ganciclovir triphosphate, which is then slowly metabolized intracellularly (half-life 18 hours). As the phosphorylation is largely dependent on the viral kinase, phosphorylation of ganciclovir occurs preferentially in virus-infected cells. The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by ganciclovir triphosphate.

Antiviral Activity

The quantitative relationship between the in vitro susceptibility of human herpesviruses to antivirals and clinical response to antiviral therapy has not been established, and virus sensitivity testing has not been standardized. Sensitivity test results, expressed as the concentration of drug required to inhibit the growth of virus in cell culture by 50% (IC ₅₀ ), vary greatly depending upon a number of factors. Thus the IC ₅₀ of ganciclovir that inhibits human CMV replication in vitro (laboratory and clinical isolates) has ranged from 0.02 to 5.75 µg/mL (0.08 to 22.94 µM). Ganciclovir inhibits mammalian cell proliferation (CIC ₅₀ ) in vitro at higher concentrations ranging from 10.21 to >250 µg/mL (40 to >1000 µM). Bone marrow-derived colony-forming cells are more sensitive (CIC ₅₀ = 0.69 to 3.06 µg/mL: 2.7 to 12 µM).

Viral Resistance

Viruses resistant to ganciclovir can arise after prolonged treatment with valganciclovir by selection of mutations in either the viral protein kinase gene (UL97) responsible for ganciclovir monophosphorylation and/or in the viral polymerase gene (UL54). Virus with mutations in the UL97 gene is resistant to ganciclovir alone, whereas virus with mutations in the UL54 gene may show cross-resistance to other antivirals with a similar mechanism of action.

The current working definition of CMV resistance to ganciclovir in in vitro assays is IC ₅₀ ≥1.5 µg/mL ( ≥6.0 µM). CMV resistance to ganciclovir has been observed in individuals with AIDS and CMV retinitis who have never received ganciclovir therapy. Viral resistance has also been observed in patients receiving prolonged treatment for CMV retinitis with ganciclovir. The possibility of viral resistance should be considered in patients who show poor clinical response or experience persistent viral excretion during therapy.