目的:我们报告了探索P2X3受体拮抗剂对味觉和咳嗽反射敏感性的影响的研究,并描述了其药代动力学,包括其CYP3A4相互作用潜力。
方法:在随机分组中,安慰剂对照,双盲研究,3×12名健康男性(18-45岁)被分配(3:1)在2周内每天两次服用filapixant(口服20、80或250mg)或安慰剂。单一剂量的咪达唑仑(1毫克),CYP3A4底物,使用和不使用filapixant。评估包括味条测试,一份口味问卷,咳嗽挑战与三磷酸腺苷,不良事件报告和标准安全性评估。
结果:味觉紊乱主要在250毫克组观察到:该组9名参与者中有6名(67%)在问卷中报告了味觉减退或味觉障碍;8名参与者(89%)报告了味觉相关的不良事件。五名参与者(56%)的总体味觉测试得分降低≥2分(点估计-1.1分,90%置信区间[-3.3;1.1])。咳嗽计数随着三磷酸腺苷浓度的增加而增加,但治疗之间没有重大差异。Filapixant暴露与剂量成比例增加。联合给药filapixant对咪达唑仑的药代动力学没有临床相关影响。浓度-时间曲线下面积比率和90%置信区间在80-125%内。未报告严重或严重不良事件。
结论:总体而言,filapixant是安全和良好的耐受性,除了温和,短暂的味觉干扰。根据(体外)受体选择性数据,这种干扰的发生频率比预期的要高,这表明P2X3:P2X2/3选择性以外的其他因素也可能在这种情况下发挥重要作用。咳嗽激发试验没有明显的治疗效果。Filapixant没有临床相关的CYP3A4相互作用潜力。
OBJECTIVE: We report on investigations exploring the P2X3-receptor antagonist filapixant\'s effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential.
METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments.
RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported.
CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.