The impact of UGT1A1 and SLCO1B1 genetic polymorphisms and pharmacokinetics of axitinib on clinical safety and efficacy in patients with metastatic renal cell carcinoma.

Abstract

448 Background: We investigated the impact of genetic polymorphisms and pharmacokinetics of axitinib on adverse events, objective responses, and survival in patients with metastatic renal cell carcinoma (mRCC). Methods: In total, 53 patients with mRCC treated with axitinib were analyzed. Patient was classified as favorable (n = 5), intermediate (n = 36), and poor (n = 12) using the MSKCC risk classification system. High-performance liquid chromatography was used to measure serum axitinib levels. AUC0–12 (ng∙h/mL) was calculated using various serum levels at 0 to 12 h (C0–C12) following administration on day 7 of treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RFLP analysis. Results: The most frequently reported ≥ G3 adverse events were hypertension (43.3%), proteinuria (30.2%), and anorexia (20.1%). The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. Patients with axitinib C0 ≥ 10 ng/mL had a significantly higher rate of hand-foot syndrome ≥ G2 and hypothyroidism ≥ G2 than those with axitinib C0 < 10 ng/mL (p = 0.013, p = 0.005). The overall survival in patients with axitinib C0 ≥ 5 ng/mL was significantly better than that in those with axitinib C0 < 5 ng/mL (p = 0.022). The mean C0 and AUC0–12 values in patients with a poor metabolizer (*6/*6, *6/*28, and *28/*28) of UGT1A1 polymorphism were significantly higher than those in patients with an extensive metabolizer (p = 0.045, p = 0.035, respectively). The mean AUC0–12 value in patients with the SLCO1B1 *15 was significantly higher than that in those without the SLCO1B1 *15 (p = 0.038). Conclusions: Serum axitinib levels were associated with adverse events and overall survival of patients with mRCC. The genetic polymorphisms in UGT1A1 and SLCO1B1 may affect serum axitinib levels in patients with mRCC. Pharmacokinetics and genetic polymorphisms play important roles in the outcomes of patients with mRCC treated with axitinib.