Hepatic intra-arterial infusion of fotemustine: pharmacokinetics

Fotemustine is a new nitrosourea derivative that contains an alpha-aminophosphonic acid and has a short half-life and a high plasma clearance. As myelosuppression occurs as the dose-limiting toxicity, local drug delivery has been investigated in the treatment of liver metastases arising from colorectal cancer. A pharmacokinetic study was undertaken in patients who received either i.v. or hepatic intra-arterial (HIA) infusion of 100 mg/m2 fotemustine so as to estimate the advantage of local chemotherapy, considering the pharmacokinetic differences between the two routes together with the resultant toxicities (when available). Our findings substantiated the hypothesis that a 4-h HIA infusion of foetmustine would result in a lower exposure of healthy tissues to the drug, since the AUC measured in systemic plasma was reduced by approximately 50% following such treatment as compared with i.v. infusion. This reduction in AUC should indicate a manyfold increase in exposure of the liver tumour to the alkylating properties of the drug, since it represents the proportion of the dose that has degraded within the liver. The first-pass liver-extraction ratio of fotemustine given as a 4-h HIA infusion, which ranged from 0.4 to 0.9 as estimated in patients receiving i.v. and HIA infusions in a cross-over study, argues for further investigation of HIA foetemustine infusion for the treatment of liver metastases so as to increase the response rate and decrease the occurrence of major toxic side effects in such patients.