title: Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients.
abstract: BACKGROUND
  Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers.
  
  
  METHODS
  Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID.
  
  
  RESULTS
  Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand-foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for ≥3 months. Abnormal TSH correlated with exposure to axitinib (r = 0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r = -0.94). Axitinib showed antitumor activity across multiple tumor types.
  
  
  CONCLUSIONS
  Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure.
authors.affiliation: Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. yufujiwa@med.kobe-u.ac.jp
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Naomi
authors.initials: N
authors.lastname: Kiyota
authors.forename: Naoko
authors.initials: N
authors.lastname: Chayahara
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Umeyama
authors.forename: Toru
authors.initials: T
authors.lastname: Mukohara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D044466:Asian People; D000077784:Axitinib; D015415:Biomarkers / Q000097:blood; D005221:Fatigue / Q000139:chemically induced* / Q000188:drug therapy; D005260:Female; D006801:Humans; D006980:Hyperthyroidism / Q000139:chemically induced*; D007037:Hypothyroidism / Q000139:chemically induced* / Q000188:drug therapy; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019009:Proto-Oncogene Proteins c-kit / Q000097:blood; D013954:Thyroglobulin / Q000097:blood; D013972:Thyrotropin / Q000097:blood / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D007093:Imidazoles; D007191:Indazoles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013972:Thyrotropin; D013954:Thyroglobulin; D000077784:Axitinib; D019009:Proto-Oncogene Proteins c-kit; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3