Sistematični pregled farmakokinetičnih lastnosti atazanavirja in vpliva na serumske vrednosti bilirubina

Kozlevčar, Maja (author), Žiberna, Lovro (mentor), Locatelli, Igor (comentor)

Atazanavir je zaviralec HIV-proteaze, ki se uporablja v kombiniranem protiretrovirusnem zdravljenju okužbe z virusom HIV. Poleg protivirusnega učinka pomembno vpliva tudi na presnovo bilirubina, saj zavira encim UGT1A1, ki sodeluje pri konjugaciji bilirubina v jetrih. Posledično se med zdravljenjem z atazanavirjem poveča koncentracija nekonjugiranega bilirubina v serumu. Namen magistrske naloge je bil izvesti dva sistematična pregleda literature, in sicer pregled farmakokinetičnih lastnosti atazanavirja ter pregled njegovega vpliva na serumske vrednosti bilirubina. Z združitvijo ugotovitev obeh pregledov smo želeli ovrednotiti povezavo med izpostavljenostjo atazanavirja in porastom bilirubina. Literaturo smo iskali v podatkovni bazi PubMed in registru ClinicalTrials.gov, pri pregledu farmakokinetike pa smo dodatno uporabili tudi dokumentacijo regulatornih agencij. Študije smo izbrali na podlagi vnaprej določenih vključitvenih in izključitvenih kriterijev ter ločeno obravnavali podatke o farmakokinetičnih parametrih atazanavirja in serumskih vrednostih bilirubina. V sistematični pregled farmakokinetike atazanavirja smo vključili 44 študij, v pregled vpliva na serumske vrednosti bilirubina pa 22 študij. Ugotovili smo, da sta ritonavir in kobicistat povezana z izrazitim povečanjem sistemske izpostavljenosti atazanavirja. Pri zdravljenju z atazanavirjem so se serumske vrednosti celokupnega bilirubina povečale in presegle zgornjo mejo referenčnega območja. Porast je bil izrazitejši pri indirektnem kot pri direktnem bilirubinu, kar je skladno z zaviranjem encima UGT1A1. Primerjava farmakokinetičnih podatkov in serumskih vrednosti bilirubina je nakazala povezavo med izpostavljenostjo atazanavirja in porastom bilirubina, vendar natančna kvantitativna opredelitev tega odnosa zaradi heterogenosti študij ni bila mogoča. Atazanavir povzroča pričakovano, pretežno nekonjugirano hiperbilirubinemijo, ki je bila po obsegu primerljiva z blago hiperbilirubinemijo pri Gilbertovem sindromu. Ugotovitve podpirajo smiselnost nadaljnjega raziskovanja kliničnega pomena tega pojava.

• Language: Slovenian
• Keywords: atazanavir, hiperbilirubinemija, UGT1A1, sistematični pregled, farmakokinetika
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: FFA - Faculty of Pharmacy
• Publisher: [M. Kozlevčar]
• Year: 2026
• PID: 20.500.12556/RUL-183662
• UDC: 615.281:616.98:578.828(043.2)
• COBISS.SI-ID: 282212355
• Publication date in RUL: 17.06.2026

Secondary language

• Language: English
• Title: Systematic review of atazanavir pharmacokinetic parameters and their impact on serum bilirubin levels

Abstract

Atazanavir is an HIV protease inhibitor used as part of combination antiretroviral therapy for the treatment of HIV infection. In addition to its antiviral effect, it also has an important impact on bilirubin metabolism, as it inhibits the UGT1A1 enzyme, which is involved in bilirubin conjugation in the liver. As a result, serum unconjugated bilirubin concentrations increase during treatment with atazanavir. The aim of this master’s thesis was to conduct two systematic literature reviews: one reviewing the pharmacokinetic properties of atazanavir and the other reviewing its effect on serum bilirubin levels. By integrating the findings of both reviews, we aimed to evaluate the relationship between atazanavir exposure and the increase in bilirubin levels. Literature was searched in the PubMed database and the ClinicalTrials.gov registry; for the pharmacokinetic review, documentation from regulatory agencies was also used. Studies were selected based on predefined inclusion and exclusion criteria, and data on atazanavir pharmacokinetic parameters and serum bilirubin levels were analyzed separately. Forty-four studies were included in the systematic review of atazanavir pharmacokinetics, and 22 studies were included in the review of its effect on serum bilirubin levels. We found that ritonavir and cobicistat were associated with a marked increase in systemic exposure to atazanavir. During treatment with atazanavir, serum total bilirubin levels increased and exceeded the upper limit of the reference range. The increase was more pronounced for indirect than for direct bilirubin, which is consistent with inhibition of the UGT1A1 enzyme. Comparison of pharmacokinetic data and serum bilirubin levels suggested an association between atazanavir exposure and the increase in bilirubin levels; however, a precise quantitative characterization of this relationship was not possible due to study heterogeneity. Atazanavir causes expected, predominantly unconjugated hyperbilirubinemia, the extent of which was comparable to mild hyperbilirubinemia observed in Gilbert syndrome. The findings support the rationale for further investigation of the clinical significance of this phenomenon.

• Keywords: atazanavir, hyperbilirubinemia, UGT1A1, systematic review, pharmacokinetics