Pharmacokinetics of BW12C and mitomycin C, given in combination in a phase 1 study in patients with advanced gastrointestinal cancer

The effect of combining the oxygen-transport-modifying drug BW12C with mitomycin C was investigated in a phase 1 study of 26 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 60 mg/kg. Dose-limiting toxicity of vomiting was experienced at doses greater...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 1993-01, Vol.32 (1), p.67-72
Main Authors: DENNIS, I. F, RAMSAY, J. R. S, WORKMAN, P, BLEEHEN, N. M
Format: Article
Language:English
Subjects:
Antineoplastic agents
Benzaldehydes - pharmacokinetics
Benzaldehydes - pharmacology
Biological and medical sciences
Chemotherapy
Drug Combinations
Drug Evaluation
Gastrointestinal Neoplasms - drug therapy
Half-Life
Humans
Medical sciences
Metabolic Clearance Rate
Mitomycin - pharmacokinetics
Neoplasm Metastasis
Pharmacology. Drug treatments
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Summary:The effect of combining the oxygen-transport-modifying drug BW12C with mitomycin C was investigated in a phase 1 study of 26 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 60 mg/kg. Dose-limiting toxicity of vomiting was experienced at doses greater than 50 mg/kg. This corresponded to whole blood levels > or = 700 micrograms/ml and to > 50% haemoglobin modification. Whole blood concentrations of BW12C and modification of the haemoglobin oxygen saturation curve were linearly dependent on dose. BW12C whole blood pharmacokinetics were best described by a one-compartment model and were clearly dose-dependent. The half-life increased from 2.1 h at a dose of 20 mg/kg to 7.2 h at a dose of 60 mg/kg. The AUC increased in a similar non-linear fashion with increasing dose. Mitomycin C was given at a fixed dose of 20 mg/m2 at the end of the BW12C infusion. Mitomycin C plasma pharmacokinetics fitted a two-compartment model, giving a mean beta half-life of 50 +/- 7 min and AUC of 1.1 +/- 0.08 micrograms/ml h, and were unaffected by the combined treatment. There was no evidence of increased mitomycin C toxicity.
ISSN:0344-5704
1432-0843
DOI:10.1007/BF00685879