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首页> 美国卫生研究院文献>Translational and Clinical Pharmacology >Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test
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Prediction of the human in vivo antiplatelet effect of S- and R-indobufen using population pharmacodynamic modeling and simulation based on in vitro platelet aggregation test

机译：使用群体药效学模型和基于体外血小板凝集试验的模拟预测S-和R-吲哚布芬的人体内抗血小板作用

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摘要

Indobufen (Ibustrin®), a reversible inhibitor of platelet aggregation, exists in two enantiomeric forms in 1:1 ratio. Here, we characterized the anti-platelet effect of S- and R-indobufen using response surface modeling using NONMEM® and predicted the therapeutic doses exerting the maximal efficacy of each enantioselective S- and R-indobufen formulation. S- and R-indobufen were added individually or together to 24 plasma samples from drug-naïve healthy subjects, generating 892 samples containing randomly selected concentrations of the drugs of 0–128 mg/L. Collagen-induced platelet aggregation in platelet-rich plasma was determined using a Chrono-log Lumi-Aggregometer. Inhibitory sigmoid I model adequately described the anti-platelet effect. The S-form was more potent, whereas the R-form showed less inter-individual variation. No significant interaction was observed between the two enantiomers. The anti-platelet effect of multiple treatments with 200 mg indobufen twice daily doses was predicted in the simulation study, and the effect of S- or R-indobufen alone at various doses was predicted to define optimal dosing regimen for each enantiomer. Simulation study predicted that 200 mg twice daily administration of S-indobufen alone will produce more treatment effect than S-and R-mixture formulation. S-indobufen produced treatment effect at lower concentration than R-indobufen. However, inter-individual variation of the pharmacodynamic response was smaller in R-indobufen. The present study suggests the optimal doses of R-and S-enantioselective indobufen formulations in terms of treatment efficacy for patients with thromboembolic problems. The proposed methodology in this study can be applied to the develop novel enantio-selective drugs more efficiently.
机译：吲哚布芬（Ibustrin®）是血小板凝集的可逆抑制剂，以两种对映体形式以1：1的比例存在。在这里，我们通过使用NONMEM®的响应表面模型表征了S-和R-吲哚布芬的抗血小板作用，并预测了治疗剂量，发挥了每种对映选择性S-和R-吲哚布芬制剂的最大功效。将S-和R-吲哚布芬单独或一起添加到从未接受过药物治疗的健康受试者的24个血浆样品中，生成892个样品，其中包含随机选择的0-128 mg / L浓度的药物。使用Chrono-log Lumi-Aggregometer测定富含血小板血浆中胶原蛋白诱导的血小板聚集。抑制性乙状结肠模型充分描述了抗血小板作用。 S-形式更有效，而R-形式显示较少的个体间差异。在两种对映异构体之间没有观察到明显的相互作用。在模拟研究中预测了200 mg吲哚布芬每日两次剂量多次治疗的抗血小板作用，并且预测了不同剂量下单独使用S-或R-吲哚布芬的作用可以确定每种对映体的最佳给药方案。模拟研究预测，每天单独两次S-吲哚布芬200 mg的治疗将比S-和R-混合物配方产生更多的治疗效果。 S-吲哚布芬产生的治疗效果低于R-吲哚布芬。但是，R-吲哚布芬的药效学反应个体间差异较小。本研究提出了R-和S-对映选择性吲哚布芬制剂在血栓栓塞问题患者的治疗效果方面的最佳剂量。这项研究中提出的方法可以更有效地应用于开发新型对映选择性药物。

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