Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial.
Pharmacodynamic model of slow reversible binding and its applications in pharmacokinetic/pharmacodynamic modeling: review and tutorial.
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DOI：
10.1007/s10928-022-09822-y
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发表时间：
2022-10
影响因子：
2.5
通讯作者：
中科院分区：
文献类型：
--
作者：
大多数药物的治疗反应是由与其受体或靶点结合的速率和程度引发的。质量作用定律描述了药物-受体复合物结合（kon）和解离（koff）的速率，其中koff/kon比率是平衡解离常数（Kd）。具有缓慢可逆结合（SRB）的药物通常表现出延迟起效和延长的药效学作用。本报告回顾了具有SRB特征的药物的证据，描述了几种此类药物先前的药代动力学/药效学（PK/PD）建模工作，提供了SRB模型的数学和性质的教程，演示了SRB模型在其他化合物中的应用，并将SRB的PK/PD拟合与其他机理模型进行了比较。我们从PubMed文献检索中确定并总结了52种体外证实SRB的药物。SRB模型模拟和观察到的PK/PD曲线显示反应延迟和延长，增加剂量/kon或降低koff导致预期最大效应更大和效应持续时间更长。单次给药后应答恢复至基线的衰退斜率几乎呈线性，拐点在较大剂量下接近限值。SRB模型新采集了坎地沙坦降压作用和诺贝斯汀抗过敏作用的文献数据。它们的PD曲线也可以用间接响应和生物相模型拟合，差异极小。SRB模型的适用性可能是常见的，但由于需要在体外确认结合动力学和PK/PD曲线与其他机制决定因素的模型的相似性，因此未得到充分重视。
Therapeutic responses of most drugs are initiated by the rate and degree of binding to their receptors or targets. The law of mass action describes the rate of drug-receptor complex association (kon) and dissociation (koff) where the ratio koff/kon is the equilibrium dissociation constant (Kd). Drugs with slow reversible binding (SRB) often demonstrate delayed onset and prolonged pharmacodynamic effects. This report reviews evidence for drugs with SRB features, describes previous pharmacokinetic/pharmacodynamic (PK/PD) modeling efforts of several such drugs, provides a tutorial on the mathematics and properties of SRB models, demonstrates applications of SRB models to additional compounds, and compares PK/PD fittings of SRB with other mechanistic models. We identified and summarized 52 drugs with in vitro-confirmed SRB from a PubMed literature search. Simulations with a SRB model and observed PK/PD profiles showed delayed and prolonged responses and that increasing doses/kon or decreasing koff led to greater expected maximum effects and a longer duration of effects. Recession slopes for return of responses to baseline after single doses were nearly linear with an inflection point that approaches a limiting value at larger doses. The SRB model newly captured literature data for the antihypertensive effects of candesartan and antiallergic effects of noberastine. Their PD profiles could also be fitted with indirect response and biophase models with minimal differences. The applicability of SRB models is probably commonplace, but underappreciated, owing to the need for in vitro confirmation of binding kinetics and the similarity of PK/PD profiles to models with other mechanistic determinants.
影响因子：
2
作者：
Erpenbeck VJ;Vets E;Gheyle L;Osuntokun W;Larbig M;Neelakantham S;Sandham D;Dubois G;Elbast W;Goldsmith P;Weiss M
通讯作者：
Weiss M