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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: a population approach.
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Pharmacokinetic-pharmacodynamic modeling of tolmetin antinociceptive effect in the rat using an indirect response model: a population approach.

机译：托美汀抗伤害感受作用在大鼠中的药代动力学药效学模型，采用间接反应模型：群体方法。

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The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.
机译：托美汀的药代动力学与抗伤害感受作用之间的关系通过采用群体方法的间接模型进行了表征。动物在右后肢关节内注射尿酸以诱导其功能障碍。一旦功能障碍完成，大鼠接受1、3.2、10、31.6、56.2或100 mg / kg的口服托美汀剂量，并同时评估其镇痛作用和血液托美汀浓度。托美汀产生剂量依赖性的功能恢复，这与血液浓度没有直接关系。基于这些反应模式以及托美汀通过抑制前列腺素的合成减少伤害感受的事实，使用了抑制性间接反应模型。使用非线性混合效应模型（NONMEM）将药代动力学（PK）和药效学（PD）数据同时拟合到一室模型和间接应答模型。使用贝叶斯分析（以人口参数作为先验估计）描述了响应的各个时间过程。预测数据和观测数据之间有很好的一致性。群体分析产生了对伤害感受反应的最大抑制作用，为76％，IC50为9.22微克/毫升。该IC50与托美汀诱导的前列腺素体外合成抑制相似（3.0微克/毫升）。目前的结果表明，使用群体方法进行的基于机制的PK-PD分析可用于量化个体反应以及反映给定药物在体内的实际作用机制。

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