GLPG1690（一种自主分泌酶抑制剂）在健康志愿者和特发性肺纤维化患者中的群体药代动力学和药效学分析。
Population Pharmacokinetic and Pharmacodynamic Analysis of GLPG1690, an Autotaxin Inhibitor, in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis.
机构信息
Galapagos SASU, 102 avenue Gaston Roussel, 93230, Romainville, France.
Pierre Fabre, Toulouse, France.
出版信息
Clin Pharmacokinet. 2019 Sep;58(9):1175-1191. doi: 10.1007/s40262-019-00755-3.
BACKGROUND AND OBJECTIVES
GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure-response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis.
METHODS
Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300-1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure-response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily.
RESULTS
The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50-1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily.
CONCLUSION
Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis.
背景和目的
GLPG1690 是一种正在开发用于治疗特发性肺纤维化的自分泌酶抑制剂。有几项出版物表明自分泌酶在控制疾病相关的肺功能和溶血磷脂酸在肺重塑过程中的作用。本文的目的是描述 GLPG1690 的暴露-反应关系，并进一步为支持特发性肺纤维化患者临床试验的剂量选择提供合理依据。
方法
在健康志愿者中进行了两项试验：在第一项试验中，GLPG1690 单剂量从 20mg 增加到 1500mg，随后以 300-1000mg 的每日多次剂量给药。在第二项试验中，评估了利福平与 600mg GLPG1690 的相互作用。在特发性肺纤维化患者中进行了第三项试验，给予 GLPG1690 600mg 每日一次，共 12 周。首先使用非线性混合效应模型描述 GLPG1690 的暴露-反应（溶血磷脂酸 C18:2 减少）关系，然后使用该模型模拟 50-1000mg 每日一次或两次给药范围内作为自分泌酶抑制的生物标志物的溶血磷脂酸 C18:2 减少。
结果
GLPG1690 的群体药代动力学和溶血磷脂酸 C18:2 反应通过一个组合的群体药代动力学和药代动力学/药效动力学模型得到了很好的描述。剂量、制剂、利福平联合给药、健康状况（健康志愿者与特发性肺纤维化患者）和基线溶血磷脂酸 C18:2 被确定为模型中的协变量。剂量对系统清除率的影响表明，GLPG1690 的暴露量呈超过剂量比例增加，模拟剂量范围为 50-1000mg 每日一次。基于模型的模拟显示，每日一次剂量大于或等于 200mg 时，溶血磷脂酸 C18:2 的减少至少为 80%。
结论
基于这些结果，选择 200 和 600mg 每日一次剂量用于特发性肺纤维化患者的未来临床试验。
Zotero 插件