Merck & Co., Inc., Rahway, New Jersey, USA.
Orlando Clinical Research Center, Orlando, Florida, USA.
J Clin Pharmacol. 2022 Nov;62(11):1435-1444. doi: 10.1002/jcph.2094. Epub 2022 Jul 7.
Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open-label, single-dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end-stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non-HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87-, 2.79-, and 3.76-fold higher exposure (area under the plasma concentration-time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98-, 4.43-, and 4.74-fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration-time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non-HD conditions. Single-dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations.
Gefapixant 是一种 P2X3 受体拮抗剂，已在难治性或不明原因的慢性咳嗽患者中显示出疗效。我们研究了肾功能损害 (RI) 对 gefapixant 50mg 单剂量给药后药代动力学 (PK) 的影响，该研究共纳入了中度 (n=6) 或重度 (n=6) RI、接受血液透析 (HD) 和非-HD 条件下的终末期肾病 (ESRD; n=6) 以及健康匹配对照者 (n=6)。在给药后 72 小时和 48 小时分别收集了 gefapixant 浓度的时间点进行了连续的血浆和尿液样本采集。线性回归分析预测，轻度、中度和重度 RI 参与者的暴露量 (血浆浓度-时间曲线下面积) 分别比健康匹配对照者高 1.87、2.79 和 3.76 倍。分类分析显示，中度 RI、重度 RI 和 ESRD 参与者的暴露量分别比健康匹配对照者高 2.98、4.43 和 4.74 倍。与健康匹配对照者相比，各种程度 RI 参与者的口服清除率和肾清除率分别降低了 66%至 90%，这解释了随着肾功能损害程度的增加，Gefapixant 的暴露量增加。与非-HD 条件相比，HD 条件下 gefapixant 的血浆浓度-时间曲线下面积和最大血浆浓度降低了约 25%。在这项研究中，单次给予 gefapixant 通常具有良好的耐受性。该试验的数据为 gefapixant 在 >2000 例难治性或不明原因慢性咳嗽患者中进行的 3 期临床试验的入组提供了信息。这些疗效和安全性数据，结合整个开发项目的群体药代动力学分析，将用于评估肾功能损害对难治性或不明原因慢性咳嗽人群的影响程度，并确定任何剂量调整建议。
