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

Cancer Chemother Pharmacol. 1993;32(1):46-52. doi: 10.1007/BF00685875.


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 x 300 to 2 x 500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination half-lives 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-1 h. 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.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Antineoplastic Agents / pharmacokinetics*
  • Bone Marrow Transplantation
  • Brain Neoplasms / metabolism*
  • Ethylene Chlorohydrin / pharmacokinetics*
  • Female
  • Glioma / metabolism*
  • Half-Life
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Nitrosourea Compounds / administration & dosage
  • Nitrosourea Compounds / pharmacokinetics*
  • Organophosphorus Compounds / administration & dosage
  • Organophosphorus Compounds / pharmacokinetics*


  • Antineoplastic Agents
  • Nitrosourea Compounds
  • Organophosphorus Compounds
  • Ethylene Chlorohydrin
  • fotemustine