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

2019
Authors
Golubović, BojanaVučićević, Katarina

Radivojević, Dragana
Vezmar-Kovačević, Sandra

Prostran, Milica

Miljković, Branislava

Article (Published version)

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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 monitoringSource:
Journal of Medical Biochemistry, 2019, 38, 3, 323-331Publisher:
- Društvo medicinskih biohemičara Srbije, Beograd i Versita
Funding / projects:
DOI: 10.2478/jomb-2018-0030
ISSN: 1452-8258
PubMed: 31156343
WoS: 000468363100010
Scopus: 2-s2.0-85056191771
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PharmacyTY - 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 . .