Novartis Institutes for Biomedical Research, Basel, Switzerland.
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Pulm Pharmacol Ther. 2019 Aug;57:101809. doi: 10.1016/j.pupt.2019.101809. Epub 2019 Jun 10.
Fevipiprant, a prostaglandin D receptor 2 antagonist, is in clinical development as a treatment for asthma. The goal of this study was to assess the potential of fevipiprant to cause drug-drug interactions (DDI) as a perpetrator, that is, by altering the pharmacokinetics (PK) of co-medications. In vitro drug interaction studies of clinically relevant drug metabolizing enzymes and transporters were conducted for fevipiprant and its acyl glucuronide (AG) metabolite. Comparison of K values with unbound systemic or portal vein steady-state plasma exposure of fevipiprant and its AG metabolite revealed the potential for inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) transporters (R-value of 5.99), while other targets including cytochrome P450 enzymes were not, or only marginally, inhibited. Consequently, an open-label, two-part, two-period, single-sequence clinical study assessed the effect of fevipiprant 450 mg QD on the pharmacokinetics of simvastatin 20 mg and rosuvastatin 20 mg, two statins with different dependency in OATP1B1-mediated hepatic uptake, in healthy adult volunteers. The study also assessed the pharmacogenetics of the SLCO1B1 gene, which encodes OATP1B1. Clinically, fevipiprant 450 mg QD showed a low potential for interaction and increased the peak concentrations of simvastatin acid and rosuvastatin by 2.23- and 1.87-fold, respectively, with little or no impact on total exposure. Genotype analysis confirmed that SLCO1B1 genotype influences statin pharmacokinetics to a similar extent either with or without fevipiprant co-administration. In summary, fevipiprant at 450 mg QD has only minor liabilities as a perpetrator for DDI.
非甾体前列腺素 DP 受体 2 拮抗剂（fevipiprant）正处于哮喘治疗的临床开发阶段。本研究旨在评估 fevipiprant 作为潜在的药物相互作用（DDI）的致剂，即通过改变合并用药的药代动力学（PK）。对 fevipiprant 及其酰基葡萄糖醛酸（AG）代谢物进行了临床相关药物代谢酶和转运体的体外药物相互作用研究。与 fevipiprant 和其 AG 代谢物的未结合全身或门静脉稳态血浆暴露相比，K 值比较表明，有机阴离子转运多肽 1B1（OATP1B1）转运体可能被抑制（R 值为 5.99），而其他靶标包括细胞色素 P450 酶则没有被抑制，或者只是轻微抑制。因此，一项开放标签、两部分、两周期、单序列的临床研究评估了 fevipiprant 450 mg QD 对健康成年志愿者中辛伐他汀 20 mg 和瑞舒伐他汀 20 mg 两种不同依赖 OATP1B1 介导的肝摄取的他汀类药物的药代动力学的影响。该研究还评估了 SLCO1B1 基因的药物遗传学，该基因编码 OATP1B1。临床研究表明，fevipiprant 450 mg QD 具有低相互作用潜力，分别使辛伐他汀酸和瑞舒伐他汀的峰浓度增加 2.23 倍和 1.87 倍，而对总暴露的影响较小或没有。基因型分析证实，SLCO1B1 基因型对他汀类药物的药代动力学影响在有无 fevipiprant 合并给药时相似。总之，fevipiprant 450 mg QD 作为 DDI 的致剂，其潜在的不良反应较小。
