General pharmacokinetic model for drugs exhibiting target-mediated drug disposition
General pharmacokinetic model for drugs exhibiting target-mediated drug disposition
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DOI：
10.1023/a:1014414520282
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发表时间：
2001-12-01
影响因子：
2.5
通讯作者：
Jusko, WJ
中科院分区：
文献类型：
--
作者：
Mager, DE;Jusko, WJ
具有高亲和力并且在很大程度上(相对于剂量)与酶、受体或转运体等药理靶点结合的药物可能表现出非线性药代动力学(PK)行为。受体介导的内吞作用等过程可能导致药物消除。通过计算机模拟和对几种治疗剂的应用，描述和探索了描述这种行为的一般PK模型。模拟结果表明，模型预测的血浆浓度-时间分布曲线为多指数分布，低剂量和相似的终端处置阶段的分布阶段较陡峭。非隔室参数总是表现出明显的V-ss和CLD随剂量的减少，但只有当结合过程产生药物消除时，表观清除量才会减少。所提出的模型很好地捕捉了醛糖还原酶抑制剂伊米瑞司他、内皮素受体拮抗剂波生坦和重组人干扰素-β1a的药物浓度的时间过程。这种类型的模型对于全面描述不同剂量相关药物的动力学具有一定的力学基础和相当大的实用价值。
Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent V-ss and CLD decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.