Poster, Podium & Video Sessions
Presentation Authors: Ryoma Igarashi*, Akita, Japan, Norihiko Tsuchiya, Yamagata, Japan, Takamitsu Inoue, Nobuhiro Fujiyama, Kazuyuki Numakura, Hiroshi Tsuruta, Hideaki Kagaya, Atsushi Maeno, Mitsuru Saito, Shintaro Narita, Takenori Nioka, Masatomo Miura, Shigeru Sato, Tomonori Habuchi, Akita, Japan
Introduction: Axitinib is approved for use in a second-line therapy for metastatic renal cell carcinoma (mRCC). The predictions of adverse events and efficacy may contribute to the development of personalized medicine. In this study, axitinib pharmacokinetics were analyzed, and the relationships between genetic polymorphisms, the frequency of adverse events, objective responses, and survival were evaluated.
Methods: A total of 53 patients with mRCC treated with axitinib were analyzed. High-performance liquid chromatography was used to measure the serum axitinib levels. AUC0-12 (ng∙h/mL) was calculated using the serum levels at 0, 2, 4, 8, and 12 h following administration (C0, C2, C4, C8, C12, respectively; ng/mL) on day 7 of the treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RELP.
Results: The axitinib trough levels (C0) were significantly correlated with AUC0-12 of axitinib. The mean C0 and AUC0-12 values in patients with UGT1A1 polymorphism of a poor metabolizer (*6/*6, *6/*28, and *28/*28) were significantly higher than in those with UGT1A1 polymorphism of an extensive metabolizer (*1/*1, *1/*6, *1/*28, *27/*28; p = 0.045 and P =0.035, respectively). The mean AUC0-12 value in patients with SLCO1B1 *15 was significantly higher than that in those without (p = 0.038). The incidence of hand-foot syndrome ≥ G2, hypothyroidism ≥ G2, increased aspartate aminotransferase ≥ G1, and increased alanine aminotransferase ≥ G1 in patients with C0 ≥ 10 ng/mL were significantly higher than that in those with C0 < 10 ng/mL (p = 0.013, P = 0.005, P = 0.037, and P = 0.005). The overall survival in patients with C0 ≥ 5 ng/mL was significantly better than that in those with C0 < 5 ng/mL (p = 0.022).
Conclusions: The UGT1A1 and SLCO1B1 were significantly associated with serum axitinib levels. Axitinib trough levels predict therapeutic response in patients with mRCC. The optimal trough level of axitinib may be 5 to 10 ng/mL to achieve an effective treatment without severe adverse events.
Source Of Funding: none