title: Association of axitinib plasma exposure and genetic polymorphisms of ABC transporters with axitinib-induced toxicities in patients with renal cell carcinoma.
abstract: OBJECTIVE
  Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors, approved for advanced renal cell carcinoma (RCC). Associations between axitinib plasma exposure, genetic polymorphisms of ABC transporters and axitinib-induced toxicities have not been adequately explored.
  
  
  METHODS
  Twenty RCC patients treated with axitinib were enrolled in this study. Blood samples were collected 0, 0.5, 1, 2, 4, and 6 h after administration of axitinib on day 1 and at steady state. Plasma concentrations of axitinib were analyzed by UPLC-MS/MS. The ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) genetic polymorphisms were determined by real-time PCR.
  
  
  RESULTS
  ABCB1 haplotype was associated with increased dose-adjusted area under the plasma concentration-time curve (AUC) of axitinib at steady state. The incidence of fatigue during therapy was associated with high AUC0-6 of axitinib (P = 0.013). The treatment period without discontinuation or dose reduction due to adverse events in patients with high AUC0-6 of axitinib was significantly shorter than for those with low AUC0-6 (P = 0.024). No significant differences were found in the frequency of adverse events among the ABCG2 genotype and ABCB1 haplotype groups.
  
  
  CONCLUSIONS
  Our results have demonstrated that adverse events leading to discontinuation or dose reduction in axitinib were associated with increased axitinib plasma exposure, but not directly with genetic polymorphisms of ABC transporters. Therefore, measurement of steady state axitinib plasma concentrations may be useful in avoiding adverse events in axitinib therapy.
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan. hk-hiroshi@med.nagoya-u.ac.jp.|Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan. hk-hiroshi@med.nagoya-u.ac.jp.
authors: Hiroshi
authors: H
authors: Kato
authors: Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Naoto
authors: N
authors: Sassa
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.|Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.
authors: Masayuki
authors: M
authors: Miyazaki
authors: Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.
authors: Mio
authors: M
authors: Takeuchi
authors: Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.
authors: Miho
authors: M
authors: Asai
authors: Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.
authors: Akane
authors: A
authors: Iwai
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.|Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.
authors: Yukihiro
authors: Y
authors: Noda
authors: Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Momokazu
authors: M
authors: Gotoh
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan.
authors: Kiyofumi
authors: K
authors: Yamada
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D007191:Indazoles / Q000009:adverse effects* / Q000097:blood* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D017211:Treatment Failure
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007093:Imidazoles; D007191:Indazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000077784:Axitinib
keywords: ABCB1; ABCG2; Adverse events; Axitinib; Pharmacokinetics; Renal cell carcinoma