Description
Bioavailability and Pharmacokinetics
Pharmacological Classification: Direct Acting Antiviral. Pharmacology: Pharmacodynamics: 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 viral protein kinase, pUL 97. 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 cell.
The virustatic activity of ganciclovir is due to inhibition of viral DNA synthesis by ganciclovir triphosphate. Pharmacokinetics: Because the measure elimination pathway for Ganciclovir is renal, dosage reductions according to Creatinine clearance are required for Valganciclovir Hydrochloride tablets. For dosing instructions in patients with renal impairment, refer to Dosage & Administration. Absorption: Valganciclovir, a prodrug of ganciclovir, is well absorbed from the gastrointestinal tract and rapidly metabolized in the intestinal wall and liver to ganciclovir. Absolute bioavailability of ganciclovir from Valganciclovir Hydrochloride tablets following administration with food was approximately 60% Ganciclovir - median Tmax. Following administration of 450 mg to 2625 mg Valganciclovir HCl tablets ranged from 1 to 2 hours. Dose proportionality with respect to Ganciclovir AUC following administration of Valganciclovir tablets was demonstrated only under fed conditions. Systemic exposure to the pro drug, Valganciclovir is transient and low and AUC24 and Cmax values are approximately 1% and 3% of those of Ganciclovir respectively. Food Effects:
When Valganciclovir Hydrochloride tablets were administrative with the high fat meal containing approximately 600 total calories (31.1 gm fat, 51.6 gm carbohydrates and 22.2 gms protein) at a dose of 875 mg once daily to 16 HIV positive subjects, the steady - sites Ganciclovir AUC increased by 30% (95% CI to 51%), and the Cmax increased by 14% (95% CI - 5% to 36%), without any prolongation in time to peak plasma concentrations (Tmax). Valganciclovir tablets should be administered with food. Distribution: Due to rapid conversion of Valganciclovir to Ganciclovir, plasma protein binding of Valganciclovir was not determined. Plasma protein binding of Ganciclovir is 1% to 2% over concentration of 0.5 and 51 microgram/ml. When Ganciclovir was administered intravenously, the steady - state volume of distribution of Ganciclovir was 0.703 ± 0.134 ltr per kg (n=69). After administration of Valganciclovir tablet, no correlation was observed between Ganciclovir AUC reciprocal weight oral dosing of Valganciclovir tablets according to weight is not required. Metabolism: Valganciclovir is hydrolyzed to Ganciclovir; no other metabolites have been detected.
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