A pharmacokinetic and pharmacodynamic analysis of drug forgiveness
A pharmacokinetic and pharmacodynamic analysis of drug forgiveness
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DOI：
10.1007/s10928-022-09808-w
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发表时间：
2022-02-13
影响因子：
2.5
通讯作者：
Lawley, Sean D.
中科院分区：
文献类型：
--
作者：
McAllister, Noel P.;Lawley, Sean D.
不坚持服药是一个主要的公共卫生问题。为了对抗不依从，一些临床医生建议使用“宽恕性”药物，即使延迟或错过剂量，也能保持疗效。哪些药代动力学（PK）和药效学（PD）因素使药物具有宽恕性？在本文中，我们通过分析不完全依从患者的线性PK/PD模型来解决这个问题。我们假设药物效应远未达到最大，并考虑了直接效应、效应室（生物期）和间接反应PD模型。我们证明，相对于临床期望的效果，平均药物效果仅仅是病人实际服用的处方剂量的一部分。因此，在这些假设下，药物宽恕不能根据平均效果来定义。我们认为，宽恕应该从效果波动的角度来理解。我们证明了PK吸收速率、PK消除速率和PD消除速率在确定效应波动时是完全等价的。我们证明上述所有结果适用于任何不依从性模式，包括迟给药、漏给药、用药假期、额外给药等。为了获得效果波动的定量估计，我们考虑了一个简单的不遵守统计模式，并分析计算了效果的变异系数。我们进一步表明，如果上述任何一种PK/PD速率足够慢，在错过剂量后服用额外的“弥补”剂量可以减少效果波动。我们举例说明了二甲双胍非线性间接响应模型的一些结果。
Nonadherence to medication is a major public health problem. To combat nonadherence, some clinicians have suggested using "forgiving" drugs, which maintain efficacy in spite of delayed or missed doses. What pharmacokinetic (PK) and pharmacodynamic (PD) factors make a drug forgiving? In this paper, we address this question by analyzing a linear PK/PD model for a patient with imperfect adherence. We assume that the drug effect is far from maximal and consider direct effect, effect compartment (biophase), and indirect response PD models. We prove that the average drug effect relative to the clinically desired effect is simply the fraction of prescribed doses actually taken by the patient. Hence, under these assumptions, drug forgiveness cannot be defined in terms of the average effect. We argue that forgiveness should instead be understood in terms of effect fluctuations. We prove that the rates of PK absorption, PK elimination, and PD elimination are exactly equivalent for determining effect fluctuations. We prove all the aforementioned results for any pattern of nonadherence, including late doses, missed doses, drug holidays, extra doses, etc. To obtain quantitative estimates of effect fluctuations, we consider a simple statistical pattern of nonadherence and analytically calculate the coefficient of variation of effect. We further show how effect fluctuations can be reduced by taking an extra "make up" dose following a missed dose if any one of the aforementioned PK/PD rates is sufficiently slow. We illustrate some of our results for a nonlinear indirect response model of metformin.