title: A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine.
abstract: OBJECTIVE
  To address tolerability and a possible pharmacologic interaction of capecitabine with sorafenib.
  
  
  METHODS
  Patients with advanced solid tumors (ECOG PS 0-1) were included. Cohort A received capecitabine 750 mg/m(2) BID and Cohort B received capecitabine 1,000 mg/m(2) BID, both for 14 days of a 21-day cycle. Steady-state PK was obtained for capecitabine alone, sorafenib alone, and in combination. Cohort C explored an alternate schedule of 7-day on/7-day off flat dose capecitabine 1,000 mg BID with continuous dosing of sorafenib 400 mg BID.
  
  
  RESULTS
  A total of 32 patients were enrolled between February 08 and April 09. Hand-foot skin reaction (HFSR) was the primary toxicity with 16 (50%) of the 32 patients experiencing grade 3 events (75% occurring during cycles 1-2). Grade 3 HFSR defined the maximum tolerated dose (MTD) of Cohort C at 1,000 mg BID flat dose of capecitabine. Other grade 3/4 toxicities were rare (diarrhea 6%, mucositis 3%, and fatigue 3%). Capecitabine did not change the C                            (max) or AUC((0-12)) of sorafenib. Co-administration of sorafenib with capecitabine 750 mg/m(2) (n = 6 patients) increased capecitabine AUC((0-12)) 15% and produced no change in the 5FU AUC((0-12)). At the capecitabine 1,000 mg/m(2) dose level (n = 12 pts), there was a 16% increase in capecitabine AUC((0-12)) and an 8% increase in 5FU AUC((0-12)). However, these trends were not statistically significant.
  
  
  CONCLUSIONS
  Co-administration of sorafenib resulted in a mild increase in capecitabine AUC, although not statistically significant. Capecitabine did not affect the exposure of sorafenib. The rate of grade 3 HFSR is concerning and limits the feasibility of prolonged dosing of sorafenib with capecitabine 1,000 mg/m(2) on the 21-day schedule.
authors.affiliation: Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN 37203, USA. jinfante@tnonc.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.forename: Cassie M
authors.initials: CM
authors.lastname: Lane
authors.forename: David R
authors.initials: DR
authors.lastname: Spigel
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage; D000069287:Capecitabine; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D060831:Hand-Foot Syndrome / Q000209:etiology*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D003841:Deoxycytidine; D009536:Niacinamide; D000069287:Capecitabine; D000077157:Sorafenib; D005472:Fluorouracil