title: Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma.
abstract: OBJECTIVE
  Sorafenib has various adverse events that can cause treatment discontinuation or dose reduction. The aim of this study was to compare the safety profile between renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) patients receiving sorafenib under real-life practice conditions. Furthermore, we investigated the relationship between sorafenib exposure and clinical outcomes.
  
  
  METHODS
  A total of 91 Japanese cancer patients (RCC, n = 21; HCC, n = 70) treated with sorafenib were enrolled. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0. Single blood samples were collected at each clinic visit and serum sorafenib concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The incidence of adverse events was analyzed according to cancer type and sorafenib concentration.
  
  
  RESULTS
  Hand-foot skin reaction (HFSR) was the most common adverse event among RCC (76 %) and HCC (66 %) patients. Elevations in hepatic transaminases and pancreatic amylase developed more frequently in patients with RCC than in those with HCC (p < 0.05), while hyperbilirubinemia and thrombocytopenia were observed more often in HCC patients than in RCC patients (p < 0.05). Pharmacokinetic data were available from 52 patients (RCC, n = 16; HCC, n = 36). HCC patients showed significantly higher dose-normalized concentrations than RCC patients (p = 0.0184). Sorafenib concentrations were significantly greater in patients with grade ≥2 HFSR and hypertension than in those not experiencing the adverse events (p = 0.0045 and 0.0453, respectively). Furthermore, receiver operating characteristic curves revealed optimal cutoff concentrations of sorafenib to predict grade ≥2 HFSR (5.78 μg/mL) and hypertension (4.78 μg/mL). In addition, a trend of prolonged overall survival was observed in HCC patients who achieved a maximal sorafenib concentration of ≥4.78 μg/mL during treatment compared with those who did not achieve the threshold concentration (12.0 vs. 6.5 months; log-rank p = 0.0824).
  
  
  CONCLUSIONS
  The results of this study suggest that the safety and pharmacokinetic profiles of sorafenib differ between Japanese cancer patients with RCC and HCC. Furthermore, the serum sorafenib concentration could be used as a guide to avoiding the development of severe HFSR while allowing prediction of the incidence of grade ≥2 hypertension in patients with RCC and HCC, and may potentially be related to the clinical efficacy of sorafenib for HCC.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8507, Japan, mfukudo@kuhp.kyoto-u.ac.jp.
authors.forename: Masahide
authors.initials: M
authors.lastname: Fukudo
authors.forename: Takuma
authors.initials: T
authors.lastname: Ito
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinsako
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kamba
authors.forename: Toshinari
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Seno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D060831:Hand-Foot Syndrome / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics*; D000077157:Sorafenib; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib