Pharmacokinetics in Humans

Only limited data on the pharmacokinetics of fostriecin in humans have been published. The available data are from a phase I oncology study that enrolled 20 patients whose tumors were unresponsive to established treatments (de Jong et al. 1997, 1999). Fostriecin was supplied by NCI as a lyophilized powder and diluted with 0.9% NaCl. It was administered daily as an intravenous infusion for 1 h on each of 5 days at 4-week intervals. The fostriecin doses used were 2, 4, 6.6, 10, 12.2, and 20 mg/m2 per day). Three patients were entered into the study at each dose level, with patients receiving the next higher dose when no limiting toxicity was noted at the previous dose. Blood samples were obtained on day 1 prior to infusion, at 30 and 45 min during and at the end of the infusion, and at 10, 20, and 30 min and 1, 1.5, 2, 4, 7 and 17 h after the end of infusion. Urine was collected before the start of infusion and again at 0-2, 2-5, and 15-18 h after the start of the infusion.

A close linear association was observed between drug dose, maximum plasma concentration, and AUC (area under the curve), suggesting linear pharmacokinetics within the dose range investigated. Plasma pharmacoki-netics was best described by a two-compartment model. Mean plasma halflife was 0.36 h (i1/2a) and 1.51 h (i1/2(g). Mean apparent total body clearance was 2.90 l/h/m2 (=48.3 ml/min/m2; 95% CI, 2.24-3.57 l/h/m2). Mean residence time was 1.19 h (95% CI, 0.41-1.97 h). The mean volume of distribu tion was 5.64 l/m2 (95% CI, 2.16-9.11 l/m2). Only approximately 15% of the fostriecin was excreted in the urine. After approximately 25 min a metabolite, postulated to be dephosphorylated fostriecin, appeared in the plasma and urine of patients receiving more than 12.2 mg/m2 fostriecin (de Jong et al. 1998, 1999).

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