Golubovic B (1), Vucicevic K (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, Serbia; (2)Nephrology Clinic, Clinical Centre of Serbia, University of Belgrade - School of Medicine, Serbia; (3)Departmant of Pharmacology, Clinical Pharmacology and Toxicology, University of Belgrade - School of Medicine, Serbia
Objectives: The aim of the study was to explore factors that significantly contribute to sirolimus (SRL) pharmacokinetic variability and develop population pharmacokinetic model using therapeutic drug monitoring (TDM) data.
Methods: TDM data of 25 adult kidney transplant patients were collected from patients’ records. All measured concentrations were trough. Pharmacokinetic analysis was performed using NONMEM® software (version 7 level 2) and Perl speaks NONMEM (version 3.5.3). A one-compartment model with first-order absorption and elimination was used as a structural model. Volume of distribution and constant absorption were fixed to literature values.
Results: Estimated typical clearance (CL/F) value was 12.1 l/h. CL/F was significantly influenced by sirolimus dose and aspartate aminotransferase (AST) as liver function parameter. The relationship between CL/F and sirolimus was best described by the power model. According to developed population pharmacokinetic model, sirolimus CL/F was decreased, in average, for 35.3% in patients with AST greater than 37 IU/l. The stability of the model and predicted performance were confirmed by bootstrap method and numerical predictive check.
Conclusions: Dose and AST levels outside the upper reference range explained in part sirolimus interindividual variability. The results from the study allow individualization of SRL dosing in routine patient care, especially useful for patients with compromised liver function.
References:
[1] Jiao Z, Shi XJ, Li ZD, Zhong MK (2009) Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients. Br J Clin Pharmacol 68 (1):47-60.
[2] Djebli N, Rousseau A, Hoizey G, Rerolle JP, Toupance O, Le Meur Y, Marquet P (2006) Sirolimus population pharmacokinetic/pharmacogenetic analysis and bayesian modelling in kidney transplant recipients. Clin Pharmacokinet 45 (11):1135-1148.
Reference: PAGE 23 () Abstr 3057 [www.page-meeting.org/?abstract=3057]
Poster: Drug/Disease modeling - Other topics