Population pharmacokinetic analysis of tacrolimus TDM data in stable kidney transplant patients
Golubović B (1), Vučićević K (1), Jovanović M (1), Radivojević D (2) , Kovačević Vezmar S (1), Prostran M (3), Miljković 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 aim of the study was to explore pharmacokinetic characteristics of tacrolimus and potential factors that significantly contribute to its variability in stable kidney transplant patients.
Methods: TDM data for period about one year after transplantation of 45 stable 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. Influences of demographic characteristics, biochemical variables and co-therapy on clearance (CL/F) were analyzed. FOCEI was used for parameters estimation and internal validation was performed.
Results: Interindividual variability of tacrolimus CL/F was best characterised by the exponential error model. Residual variability in tacrolimus concentrations was most adequately described by proportional model. Estimated typical clearance (CL/F) value was 4.27L/h. Among tested covariates significantly influences on CL/F were recorded for weight (WT) and daily dose of tacrolimus (DTAC). In the forward modelling building step inclusion of DTAC decreased OFV by 24.283, while inclusion of WT in the submodel with DTAC decreased OFV by 13.999. Omissions of these factors in backward step induced increment in OFV by 34.432 and 13.999. The mean interindividual coefficient of variability for CL/F in the final model was 14.2 %, while residual variability was 0.302. Internal validation indicated acceptable stability of the final model and precision and predictive performance.
Conclusions: In the present study tacrolimus CL/F was found to increase with WT and DTAC. Relationship between CL/F and DTAC may be due to so-called TDM effect. Other analyzed covariates did not influence tacrolimus CL/F significantly.
References:
[1] Golubović B, Vučićević K, Radivojević D, Kovačević Vezmar S, Prostran M, Miljković B. Total plasma protein effect on tacrolimus elimination in kidney transplant patients – population pharmacokinetic approach. Eur J Pharm Sci. 2014; 52: 34–40.
[2] Ahn, J.E., Birnbaum, A.K., Brundage, R.C., 2005. Inherent correlation between dose and clearance in therapeutic drug monitoring settings: possible misinterpretation in population pharmacokinetic analyses. J Pharmacokinet Pharmacodyn 32, 703-718.
