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 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.

An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab

“…Fotemustine concentration in the cerebrospinal fluid reached 23% of plasma level. Its excretion is mainly urinary and fecal excretion is minimal [4]. Regarding its adverse events, the most important toxic events are thrombocytopenia, leukopenia, and anemia, while liver and kidney toxicity are moderate [5].…”

The Combination of Carmustine Wafers and Fotemustine in Recurrent Glioblastoma Patients: A Monoinstitutional Experience

“…Numerous retrospective and prospective phase II studies showed an important activity of fotemustine in recurrent glioblastoma [6, 7] with a range of median overall survival from start of fotemustine treatment from 6 months to 11 months [7, 8]. Fotemustine (diethyl 1-{1-[3-(2-chloroethyl)-3-nitrosoureido] ethyl} phosphonate) is an alkylating [9] cytotoxic agent, belonging to the group of nitrosourea. It is characterized by elevated lipophilic properties and a low molecular weight that contribute to facilitation of its passage through the blood-brain barrier [10].…”

“…The antitumor activity of fotemustine is related to its ability to alkylate DNA. After intravenous infusion, the plasma concentration reached the steady state in 45 minutes and the plasma concentration varied between 1 and 14 ug/mL disappearing in the blood within three hours [9]. …”