Veng-Pedersen P, Widness J A, Pereira L M, Peters C, Schmidt R L, Lowe L S
College of Pharmacy, University of Iowa, Iowa City 52242, USA.
J Pharm Sci. 1995 Jun;84(6):760-7. doi: 10.1002/jps.2600840619.
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 i.v. 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) Vm (901 mU/mL/h, 19.4%) and km (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).
处置-分解分析（DDA）方法能够分离药代动力学中的整体消除和分布效应，并有助于专注于药物消除动力学的分析，且不需要对药物分布过程进行特定的结构化建模。一种计算机算法通过对DDA中卷积型积分微分方程进行积分来实现曲线拟合和动力学估计。该方法在对10名健康成年人类受试者的促红细胞生成素（Epo）非线性处置动力学分析中得到了验证，每位受试者静脉推注了10、100和500 U/kg剂量的Epo。根据米氏型非线性消除函数对非线性进行分析，同时考虑对每个受试者所有三个剂量的数据进行拟合。同时拟合得出了米氏参数（均值，%cv）Vm（901 mU/mL/h，19.4%）和km（4814 mU/mL，24.6%）的估计值。线性清除率参数定义为当药物水平降至零时接近的渐近清除率值。根据清除率比值对不同剂量下达到的非线性程度进行量化，清除率比值定义为线性清除率与给定剂量水平下遇到的最大药物浓度时估计的清除率之比。在10 U/kg剂量下，受试者的非线性程度非常小，平均清除率比值为1.07（2.1% CV）。随着剂量水平增加到100和500 U/kg，Epo消除动力学中的非线性程度在统计学上显著增加，清除率比值分别达到1.66（14% CV）和4.33（27% CV）。所有30次给药中总体消除速率参数的零值表明Epo的消除完全由非线性途径所致。
