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 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.
Dennis
I F
IF
MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, England.
Ramsay
J R
JR
Workman
P
P
Bleehen
N M
NM
D001547:Benzaldehydes / Q000493:pharmacokinetics* / Q000494:pharmacology; D004338:Drug Combinations; D004341:Drug Evaluation; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008657:Metabolic Clearance Rate; D016685:Mitomycin / Q000493:pharmacokinetics*; D009362:Neoplasm Metastasis
D001547:Benzaldehydes; D004338:Drug Combinations; D016685:Mitomycin; C039599:5-(2-formyl-3-hydroxyphenoxy)pentanoic acid