PMID: 7527856Dec 1, 1994Paper

Nonlinear pharmacokinetics of a recombinant human granulocyte colony-stimulating factor derivative (nartograstim): species differences among rats, monkeys and humans

The Journal of Pharmacology and Experimental Therapeutics
T KuwabaraY Sugiyama

Abstract

NTG is a human G-CSF derivative produced by Escherichia coli using gene-engineering techniques. The dose dependency of NTG pharmacokinetics in rats and monkeys was examined and compared with that previously reported for humans. In all species, the total clearance decreased and the mean residence time was prolonged as the intravenously administered dose of NTG was increased. At higher doses, the clearance in each species approached a constant value. This suggests that both saturable and nonsaturable processes are involved in NTG elimination. At the lowest dose, the saturable process accounted for 57% to 76% of total clearance. The plasma concentration-time profiles of NTG in rats and monkeys were analyzed by nonlinear pharmacokinetic models which contained both linear and Michaelis-Menten type elimination from the central compartment. The Km and Vmax values in rat, about 240 pM and 40 pmol/hr/kg, respectively, were comparable to those in the monkey. On the other hand, the values in humans were smaller, about 17% and 7%, respectively, than those in experimental animals. Therefore, the intrinsic clearance of saturable process (Vmax/Km) in humans was about one-half that in monkeys. To clarify the mechanism of the saturable clearanc...Continue Reading

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