CMV INFECTION

C. Washington¹, H. Welker², M. Farhan³, A. Humar^4
1Clinical Pharmacology, Roche, South San Francisco/CA/UNITED STATES OF AMERICA, ², F. Hoffman-LaRoche, Basel/SWITZERLAND, ³Virology, Roche products Limited, Welwyn Garden City/UNITED KINGDOM, ⁴Department Of Transplant Infectious Diseases, University of Alberta, Edmonton/AB/CANADA

Body: Valganciclovir (a pro-drug of ganciclovir) is indicated for the prevention of CMV disease in high-risk kidney, heart, and kidney-pancreas transplant recipients. Following oral administration, valganciclovir is rapidly absorbed (bioavailability ~ 65%) and extensively (≥ 98%) hydrolyzed to ganciclovir. The pharmacokinetic (PK) parameters of ganciclovir were investigated following prophylaxis with valganciclovir, up to 200 days in kidney transplant recipients. Methods: In IMPACT, a phase III, randomized, double-blind, placebo-controlled, multi-center study, 318 CMV D+R- kidney transplant recipients received valganciclovir prophylaxis (900 mg once daily) for either 200 or 100 days. A population PK analysis was conducted on a subgroup of patients (N=120).Plasma samples were collected up to 1 hour pre-dose, 1-2 hours post-dose, 3-5 hours post-dose, and 6-12 hours post-dose at weeks 4, 14 and 28 for ganciclovir concentration determination. An existing population PK model was successfully applied to this dataset.The PK parameters of ganciclovir were estimated using a nonlinear mixed effects modeling method. The relationship between ganciclovir exposure (AUC_0to24h) and clinical outcomes was explored. In addition, the effects of covariates on ganciclovir exposures were investigated. Results: A linear two-compartment model with first order absorption adequately described the ganciclovir PK data. The final population parameter estimates following 200 days of prophylaxis (95% CI) were: Cl/F, 12 L/hr (11. – 12.7); V/F 18.5 L (14.4– 22.6) and peripheral volume 44.4 L (40.2–48.6). These PK parameters were similar to those following 100 days of prophylaxis in this study, and consistent with those previously reported following 100 days of valganciclovir prophylaxis. There were no direct correlations between the likelihood of developing hematological adverse events (leucopenia, neutropenia, lymphopenia, anemia and thrombocytopenia) and ganciclovir exposure (AUC_0to24h). Furthermore, the incidence of CMV disease was not correlated with ganciclovir exposure. Ganciclovir exposures in these patients were above the lower limit (30 µg/ml*h) of the therapeutic range. The final PK model included three covariates; body weight and gender on volume of distribution and creatinine clearance on clearance. However, renal function (creatinine clearance) was the only clinically significant covariate. Conclusion: The PK parameters of ganciclovir from valganciclovir are well established and consistent between studies and did not change when extending prophylaxis from 100 to 200 days. The incidence of hematological adverse events was not clearly correlated with ganciclovir exposures, suggesting an influence of other factors (e.g. concomitant medications), in addition to the low number of events at any given concentration. This finding supports the investigation of other contributory factors in patients with hematological abnormalities to aid in clinical decision making. Similarly, the incidence of CMV disease was not correlated with ganciclovir exposure. This finding infers that adequate C_min was achieved in the majority of patients and that the majority of CMV disease occurred only after discontinuation of antiviral prophylaxis. The study explored a number of covariates, however, the only significant factor influencing ganciclovir exposure was creatinine clearance. Therefore, valganciclovir dose should be adjusted according to the current dosing algorithm.

Disclosure: All authors have declared no conflicts of interest.