VALGANCICLOVIR PROVIDES GANCICLOVIR PLASMA EXPOSURE SIMILAR TO IV GANCICLOVIR IN TRANSPLANT RECIPIENTS

Abstract

480 Ganciclovir (GCV) is indicated for prevention of CMV disease in transplant patients. IV GCV is inconvenient and is associated with catheter morbidity; oral GCV with low bioavailability (∼6%) necessitates large doses for efficacy. An orally administered valine ester of GCV, valganciclovir, (VGCV) has been developed that has shown a GCV bioavailability of ∼ 60%. This study was designed to identify a dose(s) of VGCV that would provide drug exposure similar to reference doses of IV or oral GCV. The IRB approved study in 28 liver transplant recipients was an open label, 4 way, randomized, cross-over design. Subjects were either CMV seropositive and 45-180 days post-transplant or were CMV seronegative with a CMV seronegative organ and 21-180 days post transplant. After informed consent, each subject was admitted to a clinical research center and received 4 treatments: A = 3g oral GCV given as 3 divided doses; or as a single dose B = 450mg VGCV; C = 900mg VGCV; or D = 5mg/kg IV GCV, given as a 1 hour infusion; in a random order, with a 3-7 day washout between treatments. Blood and urine samples were taken immediately prior to, and at intervals up to 24 hours after each treatment dose to measure GCV and VGCV concentrations. PK parameters were calculated by non-compartmental methods. One-sided equivalence testing was performed for AUC of GCV. The equivalence regions were 80%-∞ for the comparison of AUC of 450 mg VGCV (B) with the reference oral GCV (A) and 0%-125% for the comparison of the AUC of 900 mg VGCV (C) with the reference IV GCV (D). The results from analyses of variance with the factors subject, period and treatment were used to calculate two-sided 90% confidence intervals (CI) relative to reference (Table). No period or crossover effect was observed (p>0.05).TableThese results indicate that VGCV (900mg) provides GCV exposure similar to IV GCV and that VGCV (450mg) provides exposure similar to oral GCV (1gm TID). Therefore VGCV may be able to provide effective CMV prophylaxis in transplantation with once daily oral dosing. This Study was supported by Roche Products Ltd., Welwyn, UK and in part by PHS MO1RR750.