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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration
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Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: Favorable impact of dose up-titration

机译：泊尼西德（一种S1P1受体调节剂）的多剂量耐受性，药代动力学和药效学：剂量增加的有利影响

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摘要

This multiple-ascending-dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod-induced heart rate (HR) reduction and PR-prolongation. This elicited the design of an uptitration schedule in 17 subjects to a dose of 40 mg in part B. The up-titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple-dose pharmacokinetics were slightly more than dose-proportional and characterized by a time to maximum concentration and an elimination half-life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3-fold. Ponesimod caused a dose-dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic-pharmacodynamic model enabled comparing day 1 and steady-state conditions. These results warrant further investigation of ponesimod in patients.
机译：这项多剂量研究研究了Ponesimod（一种S1P1受体调节剂）和自身免疫性疾病的潜在新疗法的安全性，耐受性，药代动力学和药效学。在A部分中，有10位健康的男性和女性受试者每天一次口服口服庞西莫德（5、10或20 mg）或安慰剂7天。窦性心动过缓以及某些受试者的房室传导阻滞主要发生在给药的第一天，因为脱敏发展为庞西莫德引起的心率（HR）降低和PR延长。这就引出了B部分40 mg剂量的17位受试者的调整方案的设计。调整方案降低了HR和PQ / PR的作用。报告的不良事件主要与心脏和呼吸系统有关。更高剂量会增加呼吸作用。庞西莫德多剂量药代动力学略高于剂量比例，其特点是达到最大浓度所需的时间和消除半衰期分别从2.5到4.0小时和30.9到33.5小时不等，累积约2.3倍。庞西莫德引起总淋巴细胞计数的剂量依赖性持续降低，在停药后7天内可逆。一个药代动力学模型可以比较第1天和稳态条件。这些结果值得进一步研究患者体内的庞西莫德。

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