Total plasma protein and haematocrit influence on tacrolimus clearance in kidney transplant patients - population pharmacokinetic approach
B. Golubović (1), K. Vučićević (1), D. Radivojević (2), S. Vezmar Kovačević (1), M. Prostran (3), B. Miljković (1)
(1) Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University оf Belgrade, Serbia; (2) Nephrology Clinic, Clinical Centre of Serbia, University of Belgrade, Serbia; (3) Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Serbia
Objectives: Tacrolimus is a low-clearance drug extensively bound to erythrocytes and highly protein bound. The aim of the study was to investigate the influence of haematocrit and total plasma protein on tacrolimus (TAC) clearance (CL/F).
Methods: A total of 1999 measured trough concentration were obtained from routine therapeutic monitoring of 105 kidney transplant patients. TAC was administered two times daily as part of triple immunosuppressive therapy. Pharmacokinetic analysis was performed using a non-linear mixed-effects modelling program NONMEM® (version 7 level 2) and Perl speaks NONMEM (version 3.5.3). An one-compartment model with first-order absorption and first-order elimination as implemented in ADVAN2/TRANS2 subroutine was used to fit the concentration-time data. Based on literature data volume of distribution and absorption rate constants were fixed at 0.68 l/kg and 1.3 h-1, respectively. FOCEI was used for parameter estimation. Internal validation was performed.
Results: Interindividual variability of TAC CL/F was best described by the exponential error model, while an additive error model most adequately characterized residual variability in TAC concentrations. In the final model, mean interindividual coefficient of variability for CL/F was 15.2% and residual variability was 4.07 ng/ml. The estimate of CL/F for a typical patient was 10.02 l/h. TAC CL/F was significantly (p < 0.001) influenced by haematocrit and total protein. In the forward modelling building step inclusion of haematocrit and total protein produced decrease in OFV by 275.3 and 26.68, since omission of these covariates in the backward modelling building step induce increment in OFV by 76.93 and 15.35. According to our model, CL/F decreased with haematocrit. This study demonstrated incensement for 10.4% in tacrolimus CL/F with alteration of patients' minimal measured total protein levels to upper normal range.
Conclusions: The study described and quantified the effect of haematocrit and plasma proteins on tacrolimus clearance. The final model demonstrates the feasibility of estimation of individual tacrolimus clearance based on sparse TDM data.
References:
[1] Antignac M, Barrou B, Farinotti R, et al. Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol 2007;64(6):750-7.
[2] Staatz CE, Willis C, Taylor PJ, et al. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin Pharmacol Ther 2002;72(6):660-9.