MP16-08 CONTRIBUTION OF GENETIC POLYMORPHISMS RELATED TO AXITINIB PHARMACOKINETICS TO THE CLINICAL SAFETY AND EFFICACY IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II1 Apr 2017MP16-08 CONTRIBUTION OF GENETIC POLYMORPHISMS RELATED TO AXITINIB PHARMACOKINETICS TO THE CLINICAL SAFETY AND EFFICACY IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA Ryoma Igarashi, Norihiko Tsuchiya, Takamitsu Inoue, Nobuhiro Fujiyama, Kazuyuki Numakura, Hiroshi Tsuruta, Hideaki Kagaya, Atsushi Maeno, Mitsuru Saito, Shintaro Narita, Takenori Nioka, Masatomo Miura, Shigeru Sato, and Tomonori Habuchi Ryoma IgarashiRyoma Igarashi More articles by this author , Norihiko TsuchiyaNorihiko Tsuchiya More articles by this author , Takamitsu InoueTakamitsu Inoue More articles by this author , Nobuhiro FujiyamaNobuhiro Fujiyama More articles by this author , Kazuyuki NumakuraKazuyuki Numakura More articles by this author , Hiroshi TsurutaHiroshi Tsuruta More articles by this author , Hideaki KagayaHideaki Kagaya More articles by this author , Atsushi MaenoAtsushi Maeno More articles by this author , Mitsuru SaitoMitsuru Saito More articles by this author , Shintaro NaritaShintaro Narita More articles by this author , Takenori NiokaTakenori Nioka More articles by this author , Masatomo MiuraMasatomo Miura More articles by this author , Shigeru SatoShigeru Sato More articles by this author , and Tomonori HabuchiTomonori Habuchi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.514AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES 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. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e182 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ryoma Igarashi More articles by this author Norihiko Tsuchiya More articles by this author Takamitsu Inoue More articles by this author Nobuhiro Fujiyama More articles by this author Kazuyuki Numakura More articles by this author Hiroshi Tsuruta More articles by this author Hideaki Kagaya More articles by this author Atsushi Maeno More articles by this author Mitsuru Saito More articles by this author Shintaro Narita More articles by this author Takenori Nioka More articles by this author Masatomo Miura More articles by this author Shigeru Sato More articles by this author Tomonori Habuchi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...