Institute of Medical and Social Care Research, Dean Street, Bangor University, Bangor, North Wales LL57 1UT, United Kingdom.
J Clin Pharmacol. 2010 Jan;50(1):17-26. doi: 10.1177/0091270008329555. Epub 2009 Oct 1.
There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentration versus time curve from zero to infinity (AUC) are abstracted and analyzed by panel data regression modeling, with within-study fixed effects. Duration of drug action is defined as the time during which a pharmacodynamic effect (or response) exceeds a nominal threshold. The generalized models of all observations from 33 publications, with duration of action as the dependent variable and the logarithm of the dose (or AUC) as the explanatory variable, yield significant log-linear relationships. The regressions for individual studies are correctly specified in 27 cases; there are insufficient data for analysis in 10 studies, and a log-linear specification is deemed inappropriate in 6. Analysis of published dose-ranging studies shows that the duration of action of a drug is directly proportional to the logarithm of dose across a wide range of different drugs, extending a result that was previously documented for very few compounds.
对于具有单室药代动力学和直接、可逆作用机制的药物，其剂量与作用持续时间之间存在对数线性关系。然而，有人认为这种关系并不适用于其代谢产物具有活性或缓慢消除、动力学呈饱和状态以及具有击中-逃离效应的药物。本研究旨在检验这一假设，并通过系统评价和实证分析来量化这种关系。手工检索了 1980 年至 2005 年 4 种临床药理学杂志的所有问题，以寻找呈现 4 种或更多不同剂量的药效学反应随时间变化曲线的文章。从药代动力学研究中提取作用持续时间、剂量和从零到无穷大的血浆浓度-时间曲线下面积（AUC）的数据，并通过面板数据回归模型进行分析，采用研究内固定效应。药物作用持续时间定义为药效学效应（或反应）超过名义阈值的时间。33 篇文献的所有观察结果的广义模型，以作用持续时间为因变量，以剂量（或 AUC）的对数为自变量，得出显著的对数线性关系。在 27 个案例中，个体研究的回归得到了正确的指定；在 10 个案例中，数据不足无法进行分析，而在 6 个案例中，对数线性指定被认为不合适。对已发表的剂量范围研究的分析表明，药物的作用持续时间与剂量的对数成正比，这一结果适用于广泛的不同药物，扩展了以前仅针对少数化合物记录的结果。
