Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms

A decade of pharmacogenomics research on tyrosine kinase inhibitors in metastatic renal cell cancer: a systematic review

“…In some of the articles on sunitinib, the intermediate endpoints clearance and exposure were investigated and confirmed the hypotheses that SNPs in CYP3A4, CYP3A5, and ABCB1 influence drug exposure [22,29,36,37] (Figure 2). Sunitinib and pazopanib are metabolized by CYP3A4 and probably CYP3A5 but are not known to be metabolized by UGT1A1 [38,41,74]. Pazopanib inhibits UGT1A1 in vitro.…”

“…In pazopanib-treated patients, SNPs in UGT1A1 may cause a reduced expression of UGT1A1 and, together with the inhibitory effect of pazopanib, would result in hyperbilirubinemia. For sunitinib, however, this enhanced effect on inhibition does not apply [38,41]. Since sunitinib and pazopanib are both metabolized by the same CYP enzymes and are substrates for ABCB1 and ABCG2, one could expect to find the same SNPs in these PK-related genes to be related to pazopanib outcomes.…”

“…Only two pharmacogenetic studies on sorafenib were found in which genetic polymorphisms in ABCC2 and HLA-A were associated with high-grade skin rash and rs2071559 in VEGF-R2 was associated with PFS and OS. For axitinib, no associations were reported [40][41][42][43][44].…”

“…patients from the COMPARZ trial: a phase III, randomized, clinical trial comparing pazopanib versus sunitinib in mRCC treatment [10,41]. Subjects with an expected reduction in function of UGT1A1 based on the SNP genotypes of rs8175347 and rs4148323 (*28, *37, and *6) showed increased levels of bilirubin at baseline and had a higher risk for developing hyperbilirubinemia on treatment with either sunitinib or pazopanib.…”

“…Subjects with an expected reduction in function of UGT1A1 based on the SNP genotypes of rs8175347 and rs4148323 (*28, *37, and *6) showed increased levels of bilirubin at baseline and had a higher risk for developing hyperbilirubinemia on treatment with either sunitinib or pazopanib. None of the UGT1A1 SNPs showed an association with elevated ALT levels [41]. More recently, Xu et al [42] examined three separate patient cohorts of 186 patients on pazopanib in the first cohort, 690 patients using either pazopanib (n = 353) or sunitinib (n = 337) in the second cohort, and the third cohort comprised 88 patients on sunitinib.…”