Department of Pharmaceutics, China Pharmaceutical University, Nanjing, PR China.
Institute of Chinese Medical Sciences, University of Macau, Macau, PR China.
Eur J Pharm Sci. 2022 Aug 1;175:106208. doi: 10.1016/j.ejps.2022.106208. Epub 2022 May 14.
The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.
变异性心绞痛（VA）的发作具有昼夜节律性，其发作大多发生在午夜至清晨。因此，应根据其发作频率进行相应的时间治疗。丹参酚（TS）是丹参的生物活性成分，被用作模型药物。在心绞痛模型兔中研究了 TS 的药代动力学、药效学和 PK-PD 关系。通过测量血清肌钙蛋白 I（cTn-I）、肌酸激酶同工酶（CK-MB）、超氧化物歧化酶（SOD）和一氧化氮（NO）水平，从心脏损伤、氧化应激和血管内皮等不同方面评估了 TS 的治疗效果。此外，还使用 cTn-I 水平从基线的变化作为药效学终点来建立药效学模型。为了使 TS 的治疗效果与 VA 的发生频率同步，基于药效学/解卷积综合模型方法，模拟和计算了 TS 的理想治疗效果、血浆浓度和药物释放时间曲线。然后，根据上述计算结果开发了 TS 的缓释微丸（TS-SRPs）并进行了体外-体内评价。所建立的 TS 药效学模型能够精确地定量其作用与浓度之间的关系。然后，成功模拟和计算了 TS 的理想治疗效果、血浆浓度和释放时间曲线。经过处方优化，所制备的 TS-SRPs 表现出与相应理想制剂相似的体外和体内行为。同时，TS 的效果曲线与 VA 的发生频率同步，这意味着可以根据患者的需要提供适当的治疗效果。总之，基于综合模型方法的治疗效果定制是高效、可行和可靠的。
