Metabolism, excretion and pharmacokinetics of a single dose of [ 14 C]-raltitrexed in cancer patients

Abstract

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase and has recently been licensed in Europe for use in the treatment of advanced colorectal carcinoma. This study evaluated the metabolism, excretion and pharmacokinetics after a single dose of 3.0 mg/m2 [14C]-raltitrexed in patients with advanced solid malignancies not amenable to curative therapy. From April 1994 to July 1995, nine patients (six men and three women) were recruited into the study. Pharmacokinetics analysis was performed during the first cycle of treatment in all patients and, in two patients, limited sampling was done prior to and during the second cycle of treatment. The mean observed peak plasma concentration (Cmax) was 700.6 ng/ml and the median time (tmax) to reach maximal raltitrexed concentrations was 15 min after the initiation of the infusion. After reaching Cmax the drug declined in a triexponential manner with a terminal half-life of 257 h. The AUC0-infinity as predicted by the pharmacokinetic model was 2341.7 ng h ml(-1). Clearance was 41.3 ml/min, of which renal clearance accounted for 50-60%. Urinary collection for the measurement of radiolabeled drug revealed that renal excretion extrapolated to infinity accounted for 40% of the total radioactive dose. Faecal excretion accounted for only 3% of the dose when samples were collected to day 5 in the first six patients. Collection was extended to 10 days in the last three patients and faecal elimination accounted for 14% in these patients. Raltitrexed measurements prior to subsequent doses suggest that there was no accumulation of the drug with repeated administration. Low levels of radioactivity measured in the red cell pellets on days 15, 22 and 29 are likely to represent drug retained by newly forming red cells at the time of dosing. Examination of the urine revealed that the drug was excreted unchanged. The toxicities seen were in line with those encountered in previous studies. Grade 3 and 4 thrombocytopenia occurred in three patients and grade 3 neutropenia occurred in two patients.

Schedule‐dependent Synergism and Antagonism between Raltitrexed (“Tomudex”) and Methotrexate in Human Colon Cancer Cell Lines in vitro

“…Raltitrexed is commonly administered as a 15 min i.v. infusion and the β-and γ-half-lives are 2 and >10 h. 4,5) Clinical studies have shown that the dose-limiting toxicities of raltitrexed involve myelosuppression, malaise and gastrointestinal toxicity. 4,6) Raltitrexed has promising therapeutic activity against colon cancer and other solid tumors.…”

True

“…Recent pharmacokinetic studies suggest that up to 60% of raltitrexed clearance is accounted for by renal excretion (Clarke et al, 1996;Beale et al, 1998). It is therefore of interest that renal toxicity with the combination of raltitrexed and cisplatin was minimal.…”

Characterization of Binding of Folates and Antifolates to Brush-Border Membrane Vesicles Isolated from Human Kidney

“…The antifolates, like natural folates, are eliminated via the kidney (Azarnoff et al, 1974;Sessa et al, 1988;Beale et al, 1998;Rinaldi et al, 1999). Despite the dominant role of FRs in renal elimination of natural folates, their involvement in the renal elimination of antifolates has not been studied.…”