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

doi:10.1002/jps.2600840619

Journal of Pharmaceutical Sciences

Volume 84, Issue 6, June 1995, Pages 760-767

https://doi.org/10.1002/jps.2600840619 Get rights and content

Abstract

The disposition–decomposition analysis (DDA) methodology enables isolation of the overall elimination and distribution effects in pharmacokinetics and facilitates analysis which focuses on drug elimination kinetics and does not require a specific structured modeling of drug distribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodifferential equation in the DDA. The approach is demonstrated in an analysis of the nonlinear disposition kinetics of erythropoietin (Epo) in 10 healthy, adult human subjects who each received 10, 100, and 500 U/kg iv bolus doses of Epo. The nonlinearity is analyzed according to a Michaelis–Menten type nonlinear elimination function, considering simultaneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis–Menten parameters (mean, % CV) V_m, (901 mU/mL/h, 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 degree 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 concentration encountered at the given dose level. The subjects showed very little 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 nonlinearity 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 global elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).

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Research ArticlesKinetic Evaluation of Nonlinear Drug Elimination by a Disposition Decomposition Analysis. Application to the Analysis of the Nonlinear Elimination Kinetics of Erythropoietin in Adult Humans

Abstract

Comput. Biol. Med.

J. Pharm. Sci.

J. Pharm. Sci.

J. Pediatr.

J. Pharm. Sci.

Comparative evaluation of six techniques for determining the Michaelis‐Menten parameters relating phenytoin dose and steady‐state serum concentration

J. Pharm. Pharmacol.

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions I. Derivations and theoretical analysis.J. Pharmacokinet

Biopharm

Theorems and implications of a model independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions II

Clearance concepts applied to the evaluation of distribution kinetics. J. Pharmacokinet. Biopharm.

Theorems and implications of a model‐independent elimination/distribution function decomposition of linear and some nonlinear drug dispositions III

Peripheral bioavailability and distribution time concepts applied to the evaluation of distribution kinetics. J. Pharmacokinet. Biopharm.

Generalized pharmacokinetic modeling for drugs with nonlinear binding I

Theoretical framework. J. Pharmacokinet. Biopharm.

Research Articles
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