title: Pharmacokinetic results of a phase I trial of sorafenib in combination with dacarbazine in patients with advanced solid tumors.
abstract: OBJECTIVE
  Sorafenib, a multikinase inhibitor of Raf and several growth factor receptors, is under investigation in combination with dacarbazine, a commonly used chemotherapeutic agent for the treatment of many cancers. The current phase I study investigates the effects of sorafenib on the pharmacokinetic (PK) profile of dacarbazine and its metabolite 5-amino-imidazole-4-carboxamide (AIC). (AIC is formed in amounts equimolar to the active alkylating moiety, methane diazohydroxide, which is undetectable by known validated assays.)
  
  
  METHODS
  Patients with advanced solid tumors received intravenous dacarbazine 1,000 mg/m(2) on day 1 of a 21-day cycle to evaluate the PK of dacarbazine alone. Sorafenib 400 mg was administered twice daily continuously starting at day 2 of cycle 1. The PK of dacarbazine in the presence of sorafenib was assessed on day 1 of cycle 2. Sorafenib PK was also assessed at steady state.
  
  
  RESULTS
  PK data were available for 15 of 23 patients. With concomitant administration of sorafenib, the mean AUC and C (max) values of dacarbazine were reduced by 23 and 16%, respectively. Mean AUC and C (max) values of AIC were increased by 41 and 45%, respectively, with individual increases of up to 106 and 136%, respectively. The apparent terminal half-lives of the two compounds were not significantly influenced by sorafenib. Based on coefficients of variation, the AUC and C (max) values for sorafenib and its three metabolites were highly variable with dacarbazine coadministration.
  
  
  CONCLUSIONS
  Concomitant administration of sorafenib and dacarbazine as described above may result in decreased dacarbazine exposure but increased AIC exposure.
authors.affiliation: Bayer HealthCare AG, Research Center, Building 431, Aprather Weg, 42096 Wuppertal, Germany. erich.brendel@bayerhealthcare.com
authors.forename: Erich
authors.initials: E
authors.lastname: Brendel
authors.forename: Matthias
authors.initials: M
authors.lastname: Ludwig
authors.forename: Chetan
authors.initials: C
authors.lastname: Lathia
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Stanislas
authors.initials: S
authors.lastname: Ropert
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003606:Dacarbazine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; C032566:imidazole-4-carboxamide; D000620:Aminoimidazole Carboxamide; D003606:Dacarbazine; D000077157:Sorafenib
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):144-51
references.pmid: 16397036
references.citation: Cancer Chemother Pharmacol. 2006 May;57(5):685-92
references.pmid: 16133532
references.citation: Oncologist. 2007 Apr;12(4):426-37
references.pmid: 17470685
references.citation: Clin Lung Cancer. 2007 May;8(6):396-8
references.pmid: 17562243
references.citation: Int J Clin Pharmacol Ther. 2004 Nov;42(11):650-1
references.pmid: 15598035
references.citation: N Engl J Med. 1974 Sep 19;291(12):592-7
references.pmid: 4851001
references.citation: J Clin Oncol. 2008 Aug 1;26(22):3709-14
references.pmid: 18669456
references.citation: Clin Cancer Res. 2007 May 1;13(9):2684-91
references.pmid: 17473200
references.citation: Clin Colorectal Cancer. 2005 Sep;5(3):188-96
references.pmid: 16197622
references.citation: Ann Oncol. 2006 May;17(5):866-73
references.pmid: 16500908
references.citation: Clin Pharmacol Ther. 1976 Jun;19(6):821-4
references.pmid: 773589
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: Clin Cancer Res. 1999 Aug;5(8):2192-7
references.pmid: 10473105
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4849-57
references.pmid: 17699864
references.citation: J Clin Oncol. 2008 May 1;26(13):2178-85
references.pmid: 18445842
references.citation: Mol Cancer Ther. 2008 Oct;7(10):3129-40
references.pmid: 18852116
references.citation: J Clin Oncol. 2007 Aug 1;25(22):3296-301
references.pmid: 17664477
references.citation: J Clin Oncol. 2007 Aug 1;25(22):3288-95
references.pmid: 17664476
references.citation: Clin Cancer Res. 2007 Mar 15;13(6):1801-9
references.pmid: 17363536
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: Cancer. 1977 Sep;40(3):1010-5
references.pmid: 332319
references.citation: Eur J Cancer. 2007 Jan;43(1):55-63
references.pmid: 17095207