POPULATION PHARMACOKINETICS OF HYDROXYUREA IN CANCER-PATIENTS

The pharmacokinetics of hydroxyurea (HU) were investigated in cancer p atients after intravenous infusion or oral administration. On the basi s of the minimal value of the objective function (MVOF) and prior know ledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Mic haelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform th e nonlinear regression and provide estimates of the population paramet ers. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (V-max), 0.097 mmol h(- 1) l(-1); Michaelis constant for HU elimination (K-M), 0.323 mmol/l; r enal clearance (Cl-R), 90.8 ml/min; volume of distribution (V-d), 0.18 6 x (body weight) + 25.41; absorption rate constant (K-a,), 2.92 h(-1) ; and availability to the systemic circulation (F), 0.792. The princip al findings of the investigation are that HU undergoes nonlinear elimi nation in cancer patients and that HU is reasonably well absorbed foll owing oral administration.