Population Pharmacokinetics/Pharmacodynamics of Ganciclovir after Intravenous Ganciclovir and Oral Valganciclovir Administration in SOT Patients Infected with CMV
H. Colom 1, M.J. Garrido 3, A. Caldes 2 , I.F.Trocóniz 3, A. Padulles 2, S. Gilvernet 2, N. Lloberas 2, Y. Armendariz 2; C. Peraire 1; J. M. Grinyó 2
1 Pharmacy and Pharmaceutical Technology Department. School of Pharmacy, University of Barcelona. Spain; 2 Nefrology Service, Hospital Universitario de Bellvitge, Barcelona. Spain; 3 Pharmacy and Pharmaceutical Technology Department. School of Pharmacy, University of Navarra, Spain.
Objectives: : Cytomegalovirus (CMV) infection is the most common opportunistic infection following solid organ transplantation (SOT) that may facilitate the acute or chronic rejection. Ganciclovir (GCV) or its produg Valganciclovir (VGC), are widely used to control virions replication1. The aim of this study was to establish the population pharmacokinetics/pharmacodynamics (PK/PD) of GCV after iv GCV followed by oral VGC, in SOT recipients infected with CMV.
Methods: 20 SOT patients enrolled in the study received one hour iv infusion of 5 mg/kg/12 h of GCV for 5 days followed by oral doses of VGC (900 mg/12 h) for 16 days. Doses were adjusted by estimated of creatinine clearance (CRCL). Blood samples for PK were collected on days 5 and 15 of treatment. Viral load quantified as PCR, was determined at baseline and on days 5, 15, 21 during treatment, and on days 30, 60, 90, and 180 post-treatment. The analysis was done sequentially, first the population PK model was developed and with the individual Bayes estimates, the exposure-response model was developed (PD). All analyses were performed with NONMEM VI using the FOCE interaction method.
Results: The PK of GCV was described by a bi-compartmental model with 1st order absorption. Interindividual variability (IIV) was associated to total plasma clearance CL (33%), central distribution volume V1 (48%), absorption rate constant KA (68%) and bioavailability F (22%). CRCL covariate in CL described part of its IIV. An absorption lag time of 0.38 h was found significant. Internal model validation was done by a bootstrap analysis.
The CMV dynamic model was represented by two compartments, Infected cells (I) and free virions (V), where new virions produced from infected cells at a rate, P can either death at a rate, c, or infect new cells2. GCV acts by blocking P. This effect was modelled by an inhibitory EMAX model. The IC50, drug concentration that induced the 50% of maximal inhibitory effect (0.85±0.2), was 7.2±11.4 mg/L. This model could describe the individual decrease of viral load in most of the patients, failing in those CMV seronegative [donor (+)/ recipient (-)]. In some of them, a new viral replication peak is observed at 30-40 days post-treatment. In order to explore this effect, mechanisms corresponding to immuno status are being investigated3.
Conclusions: A population PK/PD model for GCV in SOT patients infected with CMV is being developed to describe data from CMV sero-positive and negative, simultaneously.
References:
[1] Drew WL et al. Am J Transplant (2001) 1: 307-12.
[2] Neumann AU et al. Sciences (1998) 282: 103-7.
[3] Emery VC et al. J Infect Dis (2002) 185: 1723-8.