A clinical phase I toxicity study of Ro 03-8799: plasma, urine, tumour and normal brain pharmacokinetics.
Ro 03-8799 is a lipophilic, basic 2-nitroimidazole of greater potency than misonidazole, which we have administered to 52 patients. The dose-limiting toxicity is an acute central nervous system toxicity with symptoms which include nausea, disorientation, sweating, a feeling of heat and, in one extreme case, coma. Pharmacokinetic analysis was carried out in 31 patients. The mean distribution phase half-life was 44 min and the mean elimination half-life was 6.1 h. Peak concentration was linearly related to dose over the range 0.25 g/m2 to 3 g/m2 with a mean at 1 g/m2 of 15.7 micrograms/ml. Area under the curve was also linearly related to dose and the average whole body clearance was 20.1 l/h. Urinary recovery at 24 h was 31% for the parent compound and 28% for the N-oxide metabolite. The drug is concentrated in normal brain, brain tumour and non-brain tumour to a similar extent, the respective mean tissue/plasma ratios being 381%, 329% and 355%. For a dose of 1 g/m2, tumour concentrations were 1.5 times as high as for misonidazole, and the available in vivo and in vitro sensitisation data predict as improvement of 1.8 and 3.3 times respectively.
D001254:Astrocytoma / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000139:chemically induced; D001932:Brain Neoplasms / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D006801:Humans; D007700:Kinetics; D009369:Neoplasms / Q000378:metabolism*; D009593:Nitroimidazoles / Q000097:blood / Q000378:metabolism / Q000633:toxicity*
D009593:Nitroimidazoles; C033815:pimonidazole