title: Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial.
abstract: OBJECTIVE
  To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma.
  
  
  METHODS
  The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables.
  
  
  RESULTS
  HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m(2)) was 32.2 ± 0.9 μg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear-linear relationship between area under the concentration-time curve (AUC; mean 191 ± 6 μg·h/ml) and administered dose, especially when expressed as g/m(2). The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77-0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients.
  
  
  CONCLUSIONS
  The study supports the current nimorazole dose scheduling in patients.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: hassan@oncology.dk.
authors.forename: M A
authors.initials: MA
authors.lastname: Hassan Metwally
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: J A
authors.initials: JA
authors.lastname: Jansen
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009554:Nimorazole / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D011838:Radiation-Sensitizing Agents; D009554:Nimorazole
keywords: Head and neck carcinoma; hypoxic radiosensitisation; nimorazole; pharmacokinetics; toxicity