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Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach

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2019
3338.pdf (133.6Kb)
Authors
Golubović, Bojana
Vučićević, Katarina
Radivojević, Dragana
Vezmar-Kovačević, Sandra
Prostran, Milica
Miljković, Branislava
Article (Published version)
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Abstract
Background: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM (R). The validity of the model was tested by the internal and external validation techniques. Results: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. ...According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

Keywords:
aspartate aminotransferase / kidney transplantation / pharmacokinetics / sirolimus / therapeutic drug monitoring
Source:
Journal of Medical Biochemistry, 2019, 38, 3, 323-331
Publisher:
  • Društvo medicinskih biohemičara Srbije, Beograd i Versita
Funding / projects:
  • Basic and Clinical Pharmacological research of mechanisms of action and drug interactions in nervous and cardiovascular system (RS-175023)

DOI: 10.2478/jomb-2018-0030

ISSN: 1452-8258

PubMed: 31156343

WoS: 000468363100010

Scopus: 2-s2.0-85056191771
[ Google Scholar ]
6
4
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3340
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Golubović, Bojana
AU  - Vučićević, Katarina
AU  - Radivojević, Dragana
AU  - Vezmar-Kovačević, Sandra
AU  - Prostran, Milica
AU  - Miljković, Branislava
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3340
AB  - Background: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM (R). The validity of the model was tested by the internal and external validation techniques. Results: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.
PB  - Društvo medicinskih biohemičara Srbije, Beograd i Versita
T2  - Journal of Medical Biochemistry
T1  - Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach
VL  - 38
IS  - 3
SP  - 323
EP  - 331
DO  - 10.2478/jomb-2018-0030
ER  - 
@article{
author = "Golubović, Bojana and Vučićević, Katarina and Radivojević, Dragana and Vezmar-Kovačević, Sandra and Prostran, Milica and Miljković, Branislava",
year = "2019",
abstract = "Background: Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters. Methods: The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients' records. Population analysis was performed using the software NONMEM (R). The validity of the model was tested by the internal and external validation techniques. Results: The pharmacokinetic variability was partially explained with patient's age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model. Conclusions: The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.",
publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita",
journal = "Journal of Medical Biochemistry",
title = "Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach",
volume = "38",
number = "3",
pages = "323-331",
doi = "10.2478/jomb-2018-0030"
}
Golubović, B., Vučićević, K., Radivojević, D., Vezmar-Kovačević, S., Prostran, M.,& Miljković, B.. (2019). Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach. in Journal of Medical Biochemistry
Društvo medicinskih biohemičara Srbije, Beograd i Versita., 38(3), 323-331.
https://doi.org/10.2478/jomb-2018-0030
Golubović B, Vučićević K, Radivojević D, Vezmar-Kovačević S, Prostran M, Miljković B. Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach. in Journal of Medical Biochemistry. 2019;38(3):323-331.
doi:10.2478/jomb-2018-0030 .
Golubović, Bojana, Vučićević, Katarina, Radivojević, Dragana, Vezmar-Kovačević, Sandra, Prostran, Milica, Miljković, Branislava, "Exploring sirolimus pharmacokinetic variability using data available from the routine clinical care of renal transplant patients-population pharmacokinetic approach" in Journal of Medical Biochemistry, 38, no. 3 (2019):323-331,
https://doi.org/10.2478/jomb-2018-0030 . .

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