PHARMACOKINETICS AND PHARMACODYNAMICS OF NITROSOUREA FOTEMUSTINE - A FRENCH CANCER CENTER MULTICENTRIC STUDY

The nitrosourea, fotemustine, was given intravenously in Ih constant-r ate infusion to 66 patients in a multicentric study to assess both fot emustine pharmacokinetic behaviour and the pharmacokinetic-pharmacodyn amic relationships. Depending on the tumour type treated, two administ ration and sampling protocols were used: 100 mg/m(2)/week as a convent ional dose (six samples, 44 patients) and 300-500 mg/m(2)/day as a hig h dose (10 samples, 22 patients). The 91 time-concentration curves wer e best described by either a one-(55) or a two-compartment (36) model, and their mean clearance values did not differ significantly (85.3 +/ - 6.5 and 101.3 +/- 9.5 1/h, respectively, P = 0.1727). Fotemustine ph armacokinetics were not influenced by repeated treatment (time-indepen dence) nor by dose level (dose-independence). The pharmacodynamic effe ct observed on white blood cell count was expressed by a legit regress ion model involving the area under the curve mainly and the total admi nistered dose. White blood cell toxicity could be predicted as a funct ion of the dose for a given patient with a known fotemustine clearance value.