Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas.
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.
Tranchand
B
B
Centre Léon-Bérard, Lyon, France.
Lucas
C
C
Biron
P
P
Giroux
B
B
Gordon
B
B
Richards
R
R
Solere
P
P
Roux
N
N
Evene
E
E
Mornex
F
F
D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D016026:Bone Marrow Transplantation; D001932:Brain Neoplasms / Q000378:metabolism*; D005023:Ethylene Chlorohydrin / Q000493:pharmacokinetics*; D005260:Female; D005910:Glioma / Q000378:metabolism*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D005023:Ethylene Chlorohydrin; C054368:fotemustine