Rhizoxin is a macrocyclic
lactone compound that binds to
tubulin and inhibits microtubule assembly.
Rhizoxin demonstrated preclinical anti-tumour activity against a variety of human tumour cell lines and xenograft models. Phase I evaluation found a maximum tolerated
rhizoxin dose of 2.6 mg m-2, with reversible, but dose-limiting,
mucositis, leucopenia and diarrhoea. Clinical trials were then initiated by the EORTC ECSG in
melanoma, breast, head and neck, and non-small-cell
lung cancers with the recommended phase II
rhizoxin dose of 2 mg m-2. Pharmacological studies were instituted with the phase II trials to
complement the limited pharmacokinetic data available from the phase I trial. Blood samples were obtained from 69 of 103 eligible patients enrolled in phase II
rhizoxin studies, and these were evaluable for pharmacokinetic analysis in 36 patients. Plasma
rhizoxin concentrations were determined by high-performance liquid chromatography (HPLC), and post-distribution pharmacokinetic parameters were estimated by a one-compartment model.
Rhizoxin was rapidly eliminated from plasma, with a median systemic clearance of 8.41 min-1 m-2 and an elimination half-life of 10.4 min.
Rhizoxin area under the concentration-time curve (AUC) was higher in patients obtaining a partial response or stable disease than in those with progressive disease (median 314 vs 222 ng ml-1 min; P = 0.03). As predicted from previous studies, haematological and gastrointestinal toxicity was observed, but could not be shown to be related to
rhizoxin AUC. This study demonstrated the rapid and variable elimination of
rhizoxin from the systemic circulation. The presence of pharmacodynamic relationships and the low level of systemic toxicity suggest that future trials of
rhizoxin with alternative dosage or treatment schedules are warranted.