Contribution of UGT1A1 genetic polymorphisms related to axitinib pharmacokinetics to safety and efficacy in patients with renal cell carcinoma

AbstractAxitinib is a potent second-line molecular-targeted agent for metastatic renal cell carcinoma (mRCC). Axitinib pharmacokinetics and its relation with genetic polymorphisms were evaluated to predict the adverse events (AEs) and efficacy of axitinib. We analyzed 46 patients with mRCC who were treated with axitinib. The plasma axitinib level was measured at 0, 2, 4, 8, and 12  h after administration (C0, C2, C4, C8, and C12; ng/mL) on day 7 of the treatment. Genetic polymorphisms related to axitinib pharmacokinetics, includingSLCO1B1,SLCO1B3,SLCO2B1,ABCB1,ABCG2,CYP2C19,CYP3A5, andUGT1A1, were analyzed. Axitinib C0 and AUC0 –12 in patients withUGT1A1 poor metabolisers (*6/*6,*6/*28, and*28/*28;n = 10) were significantly higher than those in patients withUGT1A1 extensive metabolisers (*1/*1,*1/*6,*1/*28, and*27/*28;n = 36) (23.6 vs. 7.8 ng/mL,p = 0.030, and 441.3 vs. 217.1 ng h/mL,p = 0.007). The cutoff levels of C0 to predict ≥ G2 hypothyroidism and ≥ G2 anorexia were 6.6 and 7.1 ng/mL, respectively (p = 0.005 andp = 0.035). The overall survival (OS) in patients with C0 >  5 ng/mL was significantly better than that in patients with C0 <  5 ng/mL (p = 0.022). Genetic polymorphisms inUGT1A1 were significantly associated with the plasma axitinib level. The plasma axitinib level was significantly associated with the frequency of AEs and OS in patients with mRCC. No direct relationship was observed betweenUGT1A1 genoty...
Source: Medical Oncology - Category: Cancer & Oncology Source Type: research