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Population pharmacokinetics of tacrolimus in adult kidney transplant recipients
Author(s) -
Staatz Christine E.,
Willis Charlene,
Taylor Paul J.,
Tett Susan E.
Publication year - 2002
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2002.129304
Subject(s) - pharmacokinetics , volume of distribution , tacrolimus , medicine , hematocrit , population , renal function , urology , nonmem , creatinine , transplantation , environmental health
Objectives The aims of this study were to investigate the population pharmacokinetics of tacrolimus in adult kidney transplant recipients and to identify factors that explain variability. Methods Population analysis was performed on retrospective data from 70 patients who received oral tacrolimus twice daily. Morning blood trough concentrations were measured by liquid chromatography‐tandem mass spectrometry. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F), with the use of NONMEM (GloboMax LLC, Hanover, Md). Factors screened for influence on these parameters were weight, age, gender, postoperative day, days of tacrolimus therapy, liver function tests, creatinine clearance, hematocrit fraction, corticosteroid dose, and potential interacting drugs. Results CL/F was greater in patients with abnormally low hematocrit fraction (data from 21 patients only), and it decreased with increasing days of therapy and AST concentrations ( P < .01). Average parameter estimates were as follows: CL/F = 31.8 L/h (hematocrit <0.33), CL/F = 24.2 L/h (hematocrit >0.33), and V/F = 2080 L. Marked interindividual variability (42% to 111%) and residual random error (3.7 ng/mL) were observed. On the basis of the derived model, a patient with normal AST (20 U/L) or high AST (200 U/L) concentrations 7 days after commencement of therapy would require a tacrolimus dose of 4.6 mg or 4.0 mg, respectively, to achieve a steady‐state trough concentration of 10 ng/mL. Conclusions The population pharmacokinetics of tacrolimus in adult kidney transplant recipients showed wide variability. Thus it is not possible to use a standard tacrolimus dose as an empiric predictor of concentration in this population. An understanding of factors that influence the pharmacokinetics of tacrolimus may assist in drug dosage decisions. Clinical Pharmacology & Therapeutics (2002) 72 , 660–669; doi: 10.1067/mcp.2002.129304