Population pharmacokinetics of hydroxyurea in cancer patients
The pharmacokinetics of hydroxyurea (HU) were investigated in cancer patients after intravenous infusion or oral administration. On the basis of the minimal value of the objective function (MVOF) and prior knowledge of the disposition of HU in animals and man, the data were best described by a one-compartment pharmacokinetic model with parallel Michaelis-Menten metabolism and first-order renal excretion. The computer program NONMEM (nonlinear mixed effects model) was used to perform the nonlinear regression and provide estimates of the population parameters. For the combined intravenous and oral data set, these parameters were estimated to be: maximal elimination rate (V max), 0.097 mmolh−1 l−1; Michaelis constant for HU elimination (K M), 0.323 mmol/1; renal clearance (Cl R), 90.8 ml/min; volume of distribution (V d), 0.186× (body weight) + 25.41; absorption rate constant (K a), 2.92 h−1; and availability to the systemic circulation (F), 0.792. The principal findings of the investigation are that HU undergoes nonlinear elimination in cancer patients and that HU is reasonably well absorbed following oral administration.