title: A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5 mg/kg q3w and 5.0 mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Patients were randomized in a 1:1 ratio to either XELOX + BV or FOLFOX-4 + BV. Blood samples for steady-state PK of BV were collected on day 1 of cycle 5 (at the earliest) for XELOX + BV treatment and day 1 of cycle 7 (at the earliest) for FOLFOX-4 + BV treatment.
  
  
  RESULTS
  A total of 64 patients were enrolled, of which 37 were eligible for PK analyses. The primary PK parameter of BV, AUC(ss(per week)), was statistically similar between the two dosing regimens with the 90% confidence interval in the commonly used no-effect boundaries of 0.8 and 1.25. The V                            (ss) and CL did not differ between the two regimens; t                            (½) during the PK cycle was also similar for both arms at approximately 16 days. These results demonstrated no clinically relevant change in BV PK when co-administered with either XELOX or FOLFOX-4. BV in combination with XELOX and FOLFOX-4 was generally well tolerated with no unexpected safety signals and no deaths. Nine patients in the XELOX + BV arm and 15 patients in the FOLFOX-4 + BV arm experienced at least one SAE (most commonly gastrointestinal disorders) which led to dose modification in 7 and 2 patients, respectively, and to premature withdrawal in 9 and 5 patients, respectively. All 64 patients experienced at least one non-serious AE. Laboratory tests and vital signs were unremarkable.
  
  
  CONCLUSIONS
  No clinically relevant differences in overall steady-state exposure of BV occurred when BV was given 7.5 mg/kg q3w in combination with XELOX or 5.0 mg/kg q2w with FOLFOX-4 in patients with mCRC, and the pharmacokinetics of BV were very similar between the two regimens. No unexpected adverse events or deaths were identified.
authors.affiliation: Department of Clinical Pharmacology, Hoffmann-La Roche, Inc., 340 Kingsland St., Nutley, NJ 07110-1199, USA. Jianguo.zhi@roche.com
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: Pierre
authors.initials: P
authors.lastname: Major
authors.forename: Ivon
authors.initials: I
authors.lastname: Burns
authors.forename: Bridget
authors.initials: B
authors.lastname: Robinson
authors.forename: Joe
authors.initials: J
authors.lastname: McKendrick
authors.forename: Karen
authors.initials: K
authors.lastname: Rittweger
authors.forename: Markus
authors.initials: M
authors.lastname: Abt
authors.forename: David
authors.initials: D
authors.lastname: Goldstein
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil