Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study
Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study
复制标题
DOI：
10.1111/bcp.12129
复制
发表时间：
2013-12-01
影响因子：
3.4
通讯作者：
Dingemanse, Jasper
中科院分区：
文献类型：
--
作者：
Brossard, Patrick;Derendorf, Hartmut;Dingemanse, Jasper
目的本研究调查了ponesimod的耐受性，安全性，药代动力学和药效学，一种新型的口服选择性鞘氨醇-1-磷酸（S1 P（1））受体调节剂在开发中用于治疗自身免疫性疾病。健康男性受试者接受1-75 mg剂量或安慰剂对照。从8 mg剂量开始，观察到心率一过性无症状降低。波那莫德的药代动力学与剂量成比例。达到最大浓度的中位时间范围为2.0至4.0 h，ponesimod消除的平均半衰期为21.7至33.4 h。食物对ponesimod药代动力学的影响最小。>= 8 mg的剂量以剂量依赖性方式降低总淋巴细胞计数。淋巴细胞计数在96小时内恢复到正常范围。开发了一个药代动力学/药效学模型，充分描述了观察到的ponesimod对总淋巴细胞计数的影响。该递增单剂量研究的结果表明，ponesimod具有免疫调节剂潜力，其药代动力学/药效学特征与每日一次给药一致。
AIMSThis study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P(1)) receptor modulator in development for the treatment of auto-immune diseases.METHODSThis was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1-75 mg or placebo control.RESULTSPonesimod was well tolerated. Starting with a dose of 8mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of >= 8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts.CONCLUSIONSSingle doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.