Assessment of drug interactions relevant to pharmacodynamic indirect response models
Assessment of drug interactions relevant to pharmacodynamic indirect response models
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DOI：
10.1007/s10928-004-8319-4
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发表时间：
2004-10-01
影响因子：
2.5
通讯作者：
Jusko, WJ
中科院分区：
文献类型：
--
作者：
Earp, J;Krzyzanski, W;Jusko, WJ
当基本药效学反应由间接机制控制时，对简单周转系统的药物相互作用进行了评估。本报告描述了由相似或不同间接机制作用的两种药物联合产生的多种可能的体内药效学效应。通过数学和模拟探讨了药物组合的各种药效学条件：(a)两种药物同时作用于产生（k(in)）或耗散（k(out)）过程，通过竞争性（4例）或非竞争性相互作用（6例）控制体内反应；(b)两种药物同时作用于不同的kin和kout过程的组合（4例）。使用了一系列不同的药物剂量组合。根据单指数配置生成血浆浓度时间曲线。使用上述条件模拟药效学反应曲线，并使用诸如效应（和基线）曲线（ABEC）值等描述符来表征。通过竞争机制的相互作用产生的净反应本质上是加性的。在同一过程中，非竞争性相互作用的反应概况是拮抗的（两种药物的作用相互对立）和协同的（两种药物产生相同的反应）。另一方面，通过相反机制（如抑制kin +刺激k(out)）非竞争性作用于产生因子和耗散因子的药物的反应特征显示出净效应的显著变化，并产生明显的药物协同作用。由ABEC值测量的两种或两种以上药物联合使用的净间接反应曲线可能看起来是“相加性”、“拮抗性”或“协同性”，这取决于剂量、它们的内在效力、相互作用的性质（竞争性或非竞争性）以及它们的作用机制。这些模型可能有助于以比旧的经验方法更合理和机械的方式解释对两种药物的药理学反应的变化。
The assessment of drug interactions for a simple turnover system when the basic pharmacodynamic response is governed by indirect mechanisms was explored. This report describes a diverse array of possible in vivo pharmacodynamic effects from a combination of two drugs acting by similar or different indirect mechanisms. Various conditions of pharmacodynamic drug combinations were explored mathematically and by simulation: ( a) interactions of two drugs acting simultaneously either on the production (k(in)) or on the dissipation (k(out)) processes controlling the in vivo response by competitive (four cases) or non-competitive interaction ( six cases); and (b) combinations of two drugs acting on separate kin and kout processes simultaneously (four cases). A range of different combinations of drug doses was used. Plasma concentration time profiles were generated according to monoexponential disposition. Pharmacodynamic response profiles were simulated using the above conditions and characterized by descriptors such as Area Between Effect (and Baseline) Curve (ABEC) values. The interaction of agents by competitive mechanisms produced net responses that were additive in nature. Response profiles for non-competitive interactions on the same process were both antagonistic (for two drugs with effects that oppose each other) and synergistic (for two drugs that produce the same response). On the other hand, response signatures for agents acting non-competitively on the production and dissipation factors by opposing mechanisms (e. g. inhibiting kin plus stimulating k(out)) showed dramatic changes in net effects and produced apparent drug synergy. Net indirect response profiles for joint use of two or more drugs measured by ABEC values may look "additive'', "antagonistic'', or "synergistic'' depending on doses, their intrinsic potencies, the nature of interaction ( competitive or non-competitive) as well as their mechanisms of action. These models may help explain changes in pharmacologic responses to two agents in a more rational and mechanistic fashion than older empirical methods.