Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas

Abstract

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I–II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III–IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2×300 to 2×500 mg/m². Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination halflives of 4.15±2.57 and 28.8±12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96±2.89 to 12.22±3.95 mg l⁻¹h. Drug clearance was independent of the dose given and equal to 109±65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r=0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.