title: Pharmacokinetic analysis and phase 1 study of MRX-1024 in patients treated with radiation therapy with or without cisplatinum for head and neck cancer.
abstract: OBJECTIVE
  A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.
  
  
  METHODS
  The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.
  
  
  RESULTS
  Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.
  
  
  CONCLUSIONS
  There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109-5010, USA. dhamm@umich.edu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Hamstra
authors.forename: Avraham
authors.initials: A
authors.lastname: Eisbruch
authors.forename: Maddireddy U R
authors.initials: MU
authors.lastname: Naidu
authors.forename: Gogula V
authors.initials: GV
authors.lastname: Ramana
authors.forename: Prasad
authors.initials: P
authors.lastname: Sunkara
authors.forename: Kathleen C M
authors.initials: KC
authors.lastname: Campbell
authors.forename: Brian D
authors.initials: BD
authors.lastname: Ross
authors.forename: Alnawaz
authors.initials: A
authors.lastname: Rehemtulla
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001682:Biological Availability; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000209:etiology; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008715:Methionine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D052016:Mucositis / Q000209:etiology; D009325:Nausea / Q000209:etiology; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000627:therapeutic use; D011878:Radiotherapy / Q000009:adverse effects / Q000379:methods; D013237:Stereoisomerism; D013280:Stomatitis / Q000209:etiology; D016896:Treatment Outcome; D014839:Vomiting / Q000209:etiology; D055815:Young Adult
chemical_list: D011838:Radiation-Sensitizing Agents; D008715:Methionine; D002945:Cisplatin