KINETIC EVALUATION OF NONLINEAR DRUG ELIMINATION BY A DISPOSITION DECOMPOSITION ANALYSIS - APPLICATION TO THE ANALYSIS OF THE NONLINEAR ELIMINATION KINETICS OF ERYTHROPOIETIN IN ADULT HUMANS

The disposition-decomposition analysis (DDA) methodology. enables isol ation of the overall elimination and distribution effects in pharmacok inetics and facilitates analysis which focuses on drug elimination kin etics and does not require a specific structured modeling of drug dist ribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodiff erential equation in the DDA. The approach is demonstrated in an analy sis of the nonlinear disposition kinetics of erythropoietin (Epo) in 1 0 healthy, adult human subjects who each received 10, 100, and 500 U/k g iv bolus doses of Epo. The nonlinearity is analyzed according to a M ichaelis-Menten type nonlinear elimination function, considering simul taneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis-Menten param eters (mean, % cv) V-m (901 mU/mUh, 19.4%) and k(m) (4814 mU/mL, 24.6% ). A linear clearance parameter is defined as the asymptotic clearance value approached when the drug level decreases toward zero. The degre e of nonlinearity reached from Various dosings was quantified in terms of a clearance ratio which is defined as the ratio between the linear clearance and the clearance estimated for the maximum drug concentrat ion encountered at the given dose level. The subjects showed very litt le nonlinearity at the 10 U/kg dosing with a mean clearance ratio of 1 .07 (2.1% CV) A statistically significant increase in the degree of no nlinearity was observed in the Epo elimination kinetics as the dosing level was increased to 100 and 500 U/kg, reaching clearance ratios of 1.66 (14% CV) and 4.33 (27% CV), respectively. A zero value for the gl obal elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).