Phase I/II tolerability/pharmacokinetic study with one-hour intravenous infusion of doxifluiridine (5?-dFUrd) 3 g/m2 VS 5 g/m2 QD x 5 per month

Publisher Website
Google Scholar
Abstract
Summary Eighteen patients with advanced solid cancer were treated with daily 5′-dFUrd infusions given over 1 h on days 1–5 of a 4-week cycle. Nine patients received 3 g/m2 5′-dFUrd daily and another nine patients 5 g/m2. One patient on 5 g/m2 5′-dFUrd was not fully evaluable for tolerability due to early death (progressive disease) 4 weeks after the first cycle. A total of 48 cycles was given. The gastrointestinal and hematological toxicity was generally mild (grade 1–2). Central neurotoxicity (ataxia, unsteadiness, diplopia, dysarthria, sometimes confusion) was observed in 7 of 8 patients on 5 g/m2 5′-dFUrd leading to premature discontinuation of treatment in 3 patients (after 2 cycles). Only 3 of the 9 patients in the 3 g/m2 group had slight signs of cerebellopathy. Typically, the reversible neurological side effects started at the end of the 2nd week of a cycle. The serum elimination kinetics of 5′-dEUrd and its metabolites 5-FU and 5′-dFUH2 have been investigated in the serum and showed very low intra- and interindividual variations. Peak concentrations of the 5′-dFUrd at the end of the infusion approximated 500 μmol/l and 1000 μmol/l for the 3 g/m2 and 5 g/m2 group, respectively. The peak of the serum 5-FU was reached at the same time, the ratio 5-FU/5′-dFUrd being around 10%. The elimination half-life time for 5-FU was protracted by a factor of 2–3 compared with the direct injection of 5-FU. Monthly infusion of 5′-dFUrd 5 mg/m2 per day on days 1–5 lead to an unacceptable frequency and degree of neurological toxicity. Similar infusions of 5′-dFUrd 3 g/m2 per day on days 1–5 were well tolerated.