Razvoj populacijskega farmakokinetičnega modela takrolimusa pri bolnikih po presaditvi pljuč

Šehić, Sanela (author), Grabnar, Iztok (mentor), Bürmen, Božena (co-mentor)

Preživetje bolnikov po presaditvi pljuč ima bistveno slabšo prognozo v primerjavi s transplantacijami drugih trdnih organov, k čemur, poleg edinstvenih fizioloških značilnosti pljuč, prispeva težavno odmerjanje imunosupresivov zaradi njihove velike farmakokinetične variabilnosti. Namen te magistrske naloge je bil ovrednotiti, kako dobro obstoječi literaturni populacijski farmakokinetični modeli za takrolimus po transplantaciji pljuč opišejo izmerjene koncentracije takrolimusa pri preiskovani populaciji pacientov. Raziskali smo tudi vplive biokemičnih, genetskih in kliničnih dejavnikov na variabilnost farmakokinetike takrolimusa, opredelili njihovo statistično značilnost ter razvili končni populacijski farmakokinetični model, ki vključuje vse značilne vplive sočasnih spremenljivk. Končni model je dvoprostorni z naslednjimi vrednostmi parametrov in njihovimi interindividualnimi variabilnostmi (IIV): ktr = 6,97 h–1 (41,1 %), CL/F = 11,4 L/h (35,6 %), V1/F = 126 L (46,4 %), V2/F = 569 L (200 %), Q/F = 41,2 L/h (70,0 %), z vključenim vplivom naslednjih sočasnih spremenljivk na očistek: čas po transplantaciji (TAT), hematokrit, serumska koncentracija kreatinina, serumska koncentracija proteinov, sočasno zdravlje z posakonazolom, vorikonazolom, metronidazolom ali flukonazolom, sočasno zdravljenje s klaritromicinom ter sočasno zdravljenje s testosteronom. Izdelan populacijski farmakokinetični model lahko prispeva k optimizaciji režimov odmerjanja takrolimusa po transplantaciji pljuč.

• Language: Slovenian
• Keywords: presaditev pljuč, takrolimus, populacijski farmakokinetični model, NONMEM
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-142976
• Publication date in RUL: 07.12.2022

Secondary language

• Language: English
• Title: Development of a tacrolimus population pharmacokinetic model in patients after lung transplantation

Abstract

Survival of patients after lung transplantation is significantly lower compared to other solid organ transplants, which may be attributed to the unique physiological characteristics of the lungs and difficult dosing of immunosuppressive drugs due to their high pharmacokinetic variability. The aim of this master's thesis was to evaluate how well the existing literature population pharmacokinetic models for tacrolimus after lung transplantation describe the measured tacrolimus concentrations in the study population. We also investigated the effects of biochemical, genetic and clinical factors on the variability of tacrolimus pharmacokinetics, determined their statistical significance, and developed a final population pharmacokinetic model that included significant covariates. The final model is a two-compartment model with the following parameter values and their IIVs: ktr = 6.97 h–1 (41.1%), CL/F = 11.4 L/h (35.6%), V1/F = 126 L (46.4%), V2/F = 569 L (200%), Q/F = 41.2 L/h (70.0 %), including the effects of the following covariates on the clearance: time after transplantation (TAT), haematocrit, serum creatinine concentration, serum protein concentration, concurrent treatment with posaconazole, voriconazole, metronidazole, or fluconazole, concurrent treatment with clarithromycin, and concurrent treatment with testosterone. The population pharmacokinetic model developed may help optimise the tacrolimus dosing regimen after lung transplantation.

• Keywords: lung transplantation, tacolimus, population pharmacokinetic model, NONMEM