@conference{
author = "Jovanović, Marija and Ćulafić, Milica and Pejić, Nina and Štulić, Miloš and Kovačević, Milena and Vezmar-Kovačević, Sandra and Miljković, Branislava and Ćulafić, Đorđe and Vučićević, Katarina",
year = "2022",
abstract = "Tacrolimus is an immunosuppressant used to prevent graft rejection after liver
transplantation. The narrow therapeutic range and great variability in pharmacokinetics
indicate the need for therapy individualization. The aim of the study was to develop and
validate the base pharmacokinetic model of tacrolimus using data collected during
therapeutic drug monitoring. The study included 29 liver transplant recipients followed up
at Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia. Using the
NONMEM® program, we analyzed tacrolimus concentrations (Ctrough) measured in whole
blood (260). Pharmacokinetics have been described as one-compartment model with first-
order absorption and elimination. Internal validation was performed using graphical
assessment, bootstrap method and visual predictive check (VPC). Typical value of oral
clearance (CL/F) was 30.4 L/h, while value of oral volume of distribution was 5770 L. The
value of the absorption rate constant was fixed at 4.48 h-1 . Interindividual variability was
best described by the exponential model, and residual by the additive model. Interindividual
variability for CL/F was 38.2%. Individual predicted concentrations (IPRED) showed better
agreement with the measured values than population predicted values (PRED). Conditional
weighted residuals (CWRES vs PRED, CWRES vs TIME) were mostly between -2 and +2
standard deviations. The parameters obtained by bootstrap analysis do not deviate
significantly from the model. Median, 5th and 95th percentiles in the VPC method mostly
were within the simulated 95% confidence interval. The obtained population
pharmacokinetic model, after additional optimization, can be used for individualization of
the tacrolimus dosing regimen in the population of liver transplant recipients., Takrolimus je imunosupresiv koji se primenjuje za prevenciju odbacivanja grafta
nakon transplantacije jetre. Uzak terapijski opseg i velika varijabilnost u farmakokinetici
ukazuju na neophodnost individualizacije terapije. Cilj istraživanja bio je razvoj i validacija
osnovnog farmakokinetičkog modela takrolimusa baziranog na podacima prikupljenim
tokom terapijskog praćenja leka. Studija je uključila 29 pacijenata sa transplantiranom
jetrom, praćenih na Klinici za gastroenterologiju i hepatologiju, Kliničkog centra Srbije.
Primenom NONMEM® programa analizirane su koncentracije takrolimusa izmerene u punoj
krvi (260), neposredno pre primene jutarnje doze (Ctrough). Farmakokinetika je opisana
jednoprostornim modelom sa resorpcijom i eliminacijom prvog reda. Interna validacija je
vršena primenom grafičke metode procene, metode umnožavanja podataka (bootstrap) i
vizuelne prediktivne provere (VPC). Procenjena tipična vrednost oralnog klirensa (CL/F)
iznosila je 30,4 L/h, dok je vrednost oralnog volumena distribucije bila 5770 L. Vrednost
konstante brzine resorpcije je fiksirana na 4,48 h-1 . Interindividualna varijabilnost je najbolje
opisana eksponencijalnim modelom, a rezidualna aditivnim modelom. Zabeležena je
interindividualna varijabilnost za CL/F od 38,2%. Predviđene individualne koncentracije
(IPRED) pokazuju bolje slaganje sa izmerenim vrednostima, nego populacione predviđene
vrednosti (PRED). Uslovni težinski reziduali (CWRES vs PRED, CWRES vs TIME) su većinom
raspoređeni između -2 i +2 standardne devijacije. Parametri dobijeni bootstrap analizom ne
odstupaju značajno od modela, dok su vrednosti medijane, 5. i 95. percentila u VPC metodi
uglavnom bile u okviru simuliranih 95% intervala pouzdanosti. Dobijeni populacioni
farmakokinetički model, može se nakon dodatne optimizacije, primeniti u svrhu
individualizacije režima doziranja takrolimusa u populaciji pacijenata sa transplantiranom
jetrom.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "A population pharmacokinetic model of tacrolimus in adult liver transplant recipients, Populacioni farmakokinetički model takrolimusa kod pacijenata sa transplantiranom jetrom",
volume = "72",
number = "4 suplement",
pages = "S298-S299",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4531"
}