Golubovic B (1), Vucicevic K (1), Jovanovic M (1), Radivojevic D (2) , Kovacevic Vezmar S (1), Prostran M (3), Miljkovic B (1)
(1) Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia (2) Nephrology Clinic, Clinical Centre of Serbia, University of Belgrade, Belgrade, Serbia (3) Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Belgrade - School of Medicine, Belgrade, Serbia
Objectives: The purpose of this study was to develop and validate a population pharmacokinetic model using routine therapeutic drug monitoring (TDM) data.
Methods: The data obtained by routine TDM of sirolimus in 25 patients over a period of one year from sirolimus treatment initiation, were collected retrospectively from patient records. Population analysis was performed using a nonlinear mixed effects modeling software NONMEM® (ver. 7.3). A one-compartment pharmacokinetic model with first-order absorption and elimination (1-COMP) with fixed volume of distribution (Vd/F) and absorption rate constant (ka) on literature values, a 1-COMP with use of priors for Vd/F and ka and their variability and two-compartment model with first-order absorption and elimination with use of priors for ka, central volume of distribution, volume distribution of peripheral compartment, intercompartmental clearance and their variabilities were tested as structural models. Interindividual variability was evaluated by an exponential model and the additive, the proportional, and the slope-intercept error models were tested for residual variability. The validity of the model was tested by the internal validation techniques.
Results: The two-compartment model with use of priors and slope-intercept residual error was selected as structural modelbased on the favorable AIC and BIC values. According to the final model typical value of sirolimus apparent clearance (CL/F) was 12.2 L/h. It was significantly influenced by age and the liver function parameter aspartate aminotransferase (AST). CL/F was found to decrease with age. According to the developed population pharmacokinetic model, sirolimus CL/F was decreased approximately 37% (95% CI 26, 48%) in patients with AST greater than 37 IU/l. The prediction- and variability-corrected visual predictive check and numerical predictive check confirmed satisfactory prediction of developed model.
Conclusions: The population modeling of TDM data with use of informative priors allowed partial explanation of the interindividual variability in CL/F.According to the developed model patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments.
References:
[1] Dansirikul C, Morris RG, Tett SE, Duffull SB. A Bayesian approach for population pharmacokinetic modelling of sirolimus. Br J Clin Pharmacol. 2006; 62: 420 – 434.
[2] Jiao Z, Shi XJ, Li ZD, Zhong MK. Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients. Br J Clin Pharmacol. 2009; 68: 47 – 60.
Reference: PAGE 25 () Abstr 5814 [www.page-meeting.org/?abstract=5814]
Poster: Drug/Disease modeling - Other topics