Population pharmacokinetics of tacrolimus in kidney transplant recipients - A model for individual dosing
Year: 2012
Type: dissertation
Study design: Observational Study
Abstract: Background: Population pharmacokinetics is the study of pharmacokinetic variability in the population. One goal of such studies is to improve individual drug treatment by identifying relationships between pharmacokinetic parameters and patient characteristics. Tacrolimus is an immunosuppressive drug used in kidney transplantation. Tacrolimus has a narrow therapeutic window and large pharmacokinetic variability both between and within patients. In addition, dose-normalized whole blood concentrations tend to increase during the first months after kidney transplantation. Therefore, individual dosing of tacrolimus is a major clinical challenge. The objective of this study was to develop a population pharmacokinetic model for tacrolimus to aid in prediction of initial dose and individual dose requirements during the first ten weeks after kidney transplantation. Methods: Twenty-nine kidney transplant recipients contributed full pharmacokinetic profiles of tacrolimus at 44 dosing occasions, and 44 patients contributed trough concentrations from the first ten weeks after kidney transplantation. A total of 1546 blood samples were analyzed. Demographic, clinical and pharmacogenetic patient characteristics were evaluated as covariates. Population pharmacokinetic modeling was performed in NONMEM 7.2®. Results: A two compartment model with first order absorption and lag time adequately described the data. Relative bioavailability was 24 % lower in females than in males and 49 % lower in CYP3A5 expressers than in CYP3A5 nonexpressers. Fat free mass was the most predictive body size metric. Whole blood concentrations of tacrolimus increased linearly with increasing hematocrit. An underlying increase in hematocrit with time after kidney transplantation largely explained the apparent time-varying pharmacokinetics of tacrolimus. In addition, relative bioavailability was 122 % higher than its lowest value immediately after transplantation, decreased to its lowest value during the first four days and subsequently increased by 31 % with an asymptote at day 60. Conclusions: Initial dose of tacrolimus should be predicted from sex, CYP3A5 genotype, fat free mass and hematocrit. Hematocrit is an important factor to predict changes in tacrolimus whole blood concentrations over time. The model may potentially aid in individual dosing of tacrolimus. Its predictive performance must be evaluated before application in clinical practice.
Author: Elisabet Størset
Language: English
Subfield: Transplantation
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2748780186