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首页> 外文期刊>Clinical drug investigation >Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα Agonist with Moderate PPARγ Agonist activity in healthy human subjects
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Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARα Agonist with Moderate PPARγ Agonist activity in healthy human subjects

机译：Saroglitazar（ZYH1）是主要的PPARα激动剂，具有中等PPARγ激动剂活性，在健康人体内具有药代动力学，安全性和耐受性

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Background and Objectives: Dyslipidaemia is a major cardiovascular risk factor associated with type 2 diabetes mellitus. Saroglitazar (ZYH1) is a novel peroxisome proliferator-activated receptor (PPAR) agonist with predominant PPARα and moderate PPARγ activity. It has been developed for the treatment of dyslipidaemia and has favourable effects on glycaemic parameters in type 2 diabetes mellitus. The objective of this phase 1 study was to evaluate the pharmacokinetics, safety and tolerability of saroglitazar in healthy human subjects. Methods: This was a randomized, double-blind, placebo-controlled, single-centre, phase I study in healthy human volunteers, and was performed in two parts; part I evaluated single ascending oral doses of saroglitazar (0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy subjects, and part II measured the effects of food and sex on the pharmacokinetics of 1 mg saroglitazar, the human equivalent efficacy dose derived from pre-clinical studies. A total of 96 subjects were enrolled in the study, which included 88 healthy male subjects in part I and 16 healthy subjects (8 males from part I of the study and 8 females) in part II. Results: Saroglitazar was rapidly and well absorbed across all doses in the single-dose pharmacokinetic study, with a median time to the peak plasma concentration (t max) of less than 1 h (range 0.63-1 h) under fasting conditions across the doses studied. The maximum plasma concentration ranged from 3.98 to 7,461 ng/mL across the dose range. The area under the plasma concentration-time curve increased in a dose-related manner. The average terminal half-life of saroglitazar was 5.6 h. Saroglitazar was not eliminated via the renal route. There was no effect of sex on the pharmacokinetics of saroglitazar, except for the terminal half-life, which was significantly shorter in females than in males. Food had a small effect on the pharmacokinetics; however, it was not consistent in males and females. Single oral doses of saroglitazar up to 128 mg were well tolerated. No serious adverse events were reported. Adverse events were generally mild and moderate in nature. Saroglitazar did not show any clinically relevant findings in clinical laboratory investigations, physical examinations, vital signs and electrocardiograms. Conclusion: The highest dose of saroglitazar evaluated in this study was 128 mg, several times the estimated therapeutic doses (1-4 mg). The pharmacokinetics of saroglitazar support a once daily dosage schedule. Saroglitazar was found to be safe and well tolerated in this study.
机译：背景与目的：血脂异常是与2型糖尿病相关的主要心血管危险因素。 Saroglitazar（ZYH1）是一种新型的过氧化物酶体增殖物激活受体（PPAR）激动剂，具有主要的PPARα和中等的PPARγ活性。已经开发出用于治疗血脂异常的药物，并且对2型糖尿病的血糖参数具有良好的效果。这项1期研究的目的是评估Saroglitazar在健康人类受试者中的药代动力学，安全性和耐受性。方法：这是一项在健康人类志愿者中进行的随机，双盲，安慰剂对照，单中心，I期研究，分为两个部分进行;第一部分评估了健康受试者中Saroglitazar的单次递增口服剂量（0.125、0.25、0.5、1、2、4、8、16、32、64和128 mg），第二部分评估了食物和性别对药代动力学的影响1 mg saroglitazar，相当于人的等效剂量，来自临床前研究。该研究总共招募了96位受试者，其中包括第一部分的88位健康男性受试者和第二部分的16位健康受试者（8位来自研究第一部分的男性和8位女性）。结果：在单剂量药代动力学研究中，Saroglitazar在所有剂量下均迅速且良好吸收，在禁食条件下，整个剂量下达到血浆峰值浓度（t max）的中值时间少于1 h（范围0.63-1 h）。研究。在整个剂量范围内，最大血浆浓度范围为3.98至7,461 ng / mL。血浆浓度-时间曲线下的面积以剂量相关的方式增加。 Saroglitazar的平均终末半衰期为5.6 h。 Saroglitazar并未通过肾脏途径消除。性别对saroglitazar的药代动力学没有影响，除了终末半衰期，女性的半衰期明显短于男性。食物对药代动力学的影响很小;但是，在男性和女性中并不一致。最高耐受剂量为128 mg的saroglitazar单次口服剂量。没有严重不良事件的报道。不良事件一般为轻度和中度。 Saroglitazar在临床实验室检查，体格检查，生命体征和心电图检查中未显示任何与临床相关的发现。结论：这项研究中评估的最高剂量的saroglitazar为128 mg，是估计治疗剂量（1-4 mg）的几倍。 Saroglitazar的药代动力学支持每天一次的剂量表。在这项研究中发现Saroglitazar是安全的且耐受性良好。

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