Population pharmacokinetics of Valganciclovir in solid organ transplant recipients infected by cytomegalovirus
Armendariz Y2, Caldes A2 , Colom H1, Gilvernet S2, Peraire C1, Domenech J1, Grinyó JM2, Wilkins J3, Karlsson M3.
1Dept. of Pharmacokinetics. Faculty of Pharmacy, University of Barcelona. Spain 2Nefrology Service, Hospital Universitario de Bellvitge, Barcelona. Spain. 3Dept. of Pharmaceutical Biosciences. Faculty of pharmacy. Uppsala University. Sweden.
Introduction and Objectives: Cytomegalovirus (CMV) is a leading cause of disease in immunocompromised subjects, as solid organ transplant recipients. Valganciclovir (VGC), a L-valyl ester prodrug of ganciclovir was developed to offer an alternative to long-term IV and low oral bioavailability of ganciclovir (GCV). The aim of this study was to establish the population pharmacokinetics of GCV after oral VGC as treatment of CMV infection in heart, liver and kidney transplant recipients, and explore the influence of patient covariates on drug disposition.
Methods: Sixteen patients (10 renal, 2 hepatic and 4 cardiac transplant) from the "Hospital Universitari de Bellvitge" were eligible for this study. The demographic and biochemical data were recorded. Patients received 5 mg/kg/12 h of GCV for five days over a 1 hour intravenous infusion followed by oral VGC doses (900 mg/12 h) given for 15 days. In both cases doses were adjusted by creatinine clearance (CRCL). Blood samples were collected during 12 h post-dosing. A population pharmacokinetic (PK) analysis was performed using NONMEM V.
Results: As previously reported (1), the PK of GCV was best described by a two compartment open model with elimination from the central compartment. Interindividual variability (IIV),modelled as log-normally distributed, was included in total plasma clearance (25.0%),central distribution volume (52%), absorption rate (74%) and bioavailability (17.4%). Residual variability consisted of combined error (additive:0.44; proportional:16.2%) and IIV was included in it (35%). FOCE INTERACTION estimation method was used. A covariate model based on CRCL in clearance and body weight in distribution volumes was the most appropriate model to describe part of the interindividual variability . The final estimates of PK parameters (CL,total plasma clearance;V1 and V2, volumes of distribution of the central, and peripheral compartments, respectively, CLD1 intercompartmental clearance, bioavailability F, absorption rate constant KA and lagtime LT), were CL=0.15*CRCL L/h, V1=34.3*(WT/65) L, V2=29.9*(WT/65) L, CLD1=9.14 L/h, F=0.876, KA=0.961 h-1 and LT=0.385 h, respectively.
Conclusion: A population PK model for GCV, after GCV iv and VGC po, has been developed. It incorporates measure of renal function to predict total drug clearance. Validation of this model with external patients should be performed in order to assess the suitability of further GCV therapeutic drug monitoring.
References
1. Czock D. et al. Pharmacokinetics of valganciclovir and ganciclovir in renal impairment. Clin Pharmacol Ther 2002;72:142-150.