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LL-D49194 alpha 1 is a new cytotoxic antibiotic selected for clinical phase I study because of its impressive pre-clinical anti-tumour activity and its low toxicity profile in experimental animals. A total of 15 patients were treated in centres in Glasgow and Amsterdam at doses ranging from 0.25 to 4 mg/m2. One minor response was noted in a patient with colonic carcinoma. The study was suspended following the discovery of unexpected cardiotoxicity. As this toxicity was not consistent with the standard (EORTC) European Organisation for Research and Treatment of Cancer toxicology profile, we chose to investigate the pharmacokinetics of LL-D49194 alpha 1 in mice and humans in more detail to try to explain this phenomenon. A major difference in plasma protein binding was discovered between mice and patients, with a suggestion of non-linear kinetics being noted at higher doses in humans. It is likely that these differences in drug handling account for the unexpected and serious toxicity encountered in this trial.

Original publication

DOI

10.1007/bf00686154

Type

Journal article

Journal

Cancer Chemother Pharmacol

Publication Date

1993

Volume

31

Pages

395 - 400

Keywords

Aged, Aminoglycosides, Animals, Anti-Bacterial Agents, Antibiotics, Antineoplastic, Blood Proteins, Carbohydrate Sequence, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Male, Mice, Mice, Inbred BALB C, Middle Aged, Molecular Sequence Data, Neoplasms, Protein Binding, Retrospective Studies, Sensitivity and Specificity