Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck
{"title":"卡博替尼会诱发携带 UGT1A1*28 多态性的肾细胞癌患者出现孤立的高胆红素血症","authors":"Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck","doi":"10.1016/j.clgc.2024.102180","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Genetic variants of <em>UGT1A1</em>, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the <em>UGT1A1*28</em> polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.</p></div><div><h3>Methods</h3><p>We genotyped the <em>UGT1A1*28</em> TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia.</p></div><div><h3>Results</h3><p>Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (<em>P</em> < .0001), cabozantinib (<em>P</em> < .0001), and axitinib (<em>P</em> = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (<em>P</em> < .0001) or cabozantinib (<em>P</em> < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (<em>P</em> = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (<em>P</em> = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (<em>P</em> < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (<em>P</em> = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.</p></div><div><h3>Conclusion</h3><p>We validate the previously described impact of the <em>UGT1A1*28</em> polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with <em>UGT1A1</em> and causes isolated bilirubin increase.</p></div>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism\",\"authors\":\"Sajedeh Mobaraki , Peter Henrik Nissen , Frede Donskov , Agnieszka Wozniak , Yannick Van Herck , Lina Coosemans , Tine van Nieuwenhuyse , Diether Lambrechts , Oliver Bechter , Marcella Baldewijns , Eduard Roussel , Annouschka Laenen , Benoit Beuselinck\",\"doi\":\"10.1016/j.clgc.2024.102180\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Genetic variants of <em>UGT1A1</em>, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the <em>UGT1A1*28</em> polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.</p></div><div><h3>Methods</h3><p>We genotyped the <em>UGT1A1*28</em> TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia.</p></div><div><h3>Results</h3><p>Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (<em>P</em> < .0001), cabozantinib (<em>P</em> < .0001), and axitinib (<em>P</em> = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (<em>P</em> < .0001) or cabozantinib (<em>P</em> < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (<em>P</em> = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (<em>P</em> = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (<em>P</em> < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (<em>P</em> = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.</p></div><div><h3>Conclusion</h3><p>We validate the previously described impact of the <em>UGT1A1*28</em> polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with <em>UGT1A1</em> and causes isolated bilirubin increase.</p></div>\",\"PeriodicalId\":2,\"journal\":{\"name\":\"ACS Applied Bio Materials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2024-07-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Bio Materials\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1558767324001514\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"MATERIALS SCIENCE, BIOMATERIALS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1558767324001514","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism
Background
Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib.
Methods
We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia.
Results
Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed.
Conclusion
We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.