Gouyette A, Kerr D J, Kaye S B, Setanoians A, Cassidy J, Bradley C, Forrest G, Soukop M
Clinical Pharmacology Unit (UA147 CNRS and U140 INSERM), Institut Gustave-Roussy, Villejuif, France.
Cancer Chemother Pharmacol. 1988;22(2):114-9. doi: 10.1007/BF00257307.
Flavone acetic acid pharmacokinetics were studied in 31 patients in a phase I clinical trial. The drug was given by i.v. infusions over 1, 1.5, 3, and 6 h at doses ranging from 0.5 to 6.4 g/m2. The pharmacokinetic parameters were determined according to a nonlinear model including Michaelis-Menten-type kinetics. The mean elimination half-life is 4.8 h and the mean volume of distribution of the central compartment, 7.61. Our model predicted a maximal tolerated dose (MTD) of 11.1 g/m2 on the basis of the "therapeutic window" concept, very close to the clinically observed MTD of 10 g/m2. This model is also operational when different protocols of inoculation are considered, such as a divided-dose schedule vs a unique infusion, and indicates that, at the MTD, injections should be made every 72 h to avoid drug accumulation.
