Pharmacokinetic model of target-mediated disposition of thrombopoietin

被引：11

作者：

Jin F. ^{[1
]}

Krzyzanski W. ^{[1
]}

机构：

[1] Department of Pharmaceutical Science, School of Pharmacy/Pharmaceut. Sci., State Univ. of New York at Buffalo, Buffalo, NY 14260

来源：

AAPS PharmSci | / 6卷 / 1期

基金：

美国国家卫生研究院;

关键词：

Pharmacodynamic model; Receptor-mediated drug disposition; Thrombopoietin;

D O I：

10.1208/ps060109

中图分类号：

学科分类号：

摘要：

Thrombopoietin, TPO, a 353 amino acid cytokine, is a primary regulator of platelet production that was cloned recently. A target-mediated (platelet receptors) pharmacokinetic model was developed to characterize the disposition of TPO. Receptor-mediated endocytosis was assigned as the major elimination pathway in the model. A nonspecific binding compartment was also incorporated into the model. TPO concentration vs time profiles from a published phase 1 and 2 clinical trial were used to apply this model. Noncompartmental analysis demonstrated that TPO exhibits nonlinear kinetics. The proposed model captured the concentration-time profiles relatively well. The first-order internalization rate constant was estimated as 0.1 h-1. The endogenous binding capacity was estimated as 164.0 pM. The second-order binding association constant (kon) was 0.055 h-1·pM-1 and the first-order dissociation constant (koff) was estimated as 2.5 h-1, rendering the equilibrium dissociation constant Kd as 45.5 pM. This model may be relevant to other therapeutic agents with receptor-mediated endocytotic disposition.

引用

共 35 条

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