Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients

Abstract

The pharmacokinetics of an orally administered valine ester of ganciclovir (GCV), valganciclovir (VGC), were studied. These were compared to the pharmacokinetics of oral and intravenous GCV. Twenty-eight liver transplant recipients received, in an open-label random order with a 3- to 7-day washout, each of the following: 1 g of oral GCV three times a day; 450 mg of VGC per os (p.o.) once a day (q.d.); 900 mg of VGC p.o. q.d.; and 5 mg of intravenous (i.v.) GCV per kg of body weight q.d., given over 1 h. GCV and VGC concentrations were measured in blood over 24 h. One-sided equivalence testing was performed to test for noninferiority of 450 mg of VGC relative to oral GCV (two-sided 90% confidence interval [CI] > 80%) and nonsuperiority of 900 mg of VGC relative to i.v. GCV (two-sided 90% CI < 125%). The exposure of 450 mg of VGC (20.56 microg. h/ml) was found to be noninferior to that of oral GCV (20.15 microg. h/ml; 90% CI for relative bioavailability of 95 to 109%), and the exposure of 900 mg of VGC (42.69 microg. h/ml) was found to be nonsuperior to that of i.v. GCV (47.61 microg. h/ml; 90% CI = 83 to 97%). Oral VGC delivers systemic GCV exposure equivalent to that of standard oral GCV (at 450 mg) or i.v. GCV (at 900 mg of VGC). VGC has promise for effective CMV prophylaxis or treatment with once-daily oral dosing in transplant recipients.

FIG. 1

Mean plasma pharmacokinetic profiles following dosing with i.v. GCV, oral GCV, and VGC. Solid symbols are mean plasma drug concentrations (on a log scale) over the 24-h dosing interval of GCV after i.v. GCV (⧫), oral GCV (●), 450 mg of oral VGC (■), or 900 mg of oral VGC (▴). Open symbols are plasma VGC concentrations after 450 mg of oral VGC (□) and 900 mg of oral VGC (▵). Plasma VGC concentrations were only measured and reported for patients dosed with VGC. A dose-dependent increase in GCV concentration was seen after dosing with VGC. The amount of unmetabolized VGC was substantially less than that of GCV (<3%).