O'Riordan Thomas G, Donn Karl H, Hodsman Peter, Ansede John H, Newcomb Terry, Lewis Sandra A, Flitter William D, White Vicki Shigekane, Johnson M Ross, Montgomery A Bruce, Warnock David G, Boucher Richard C
1 Gilead Sciences Inc. , Seattle, WA 98102.
J Aerosol Med Pulm Drug Deliv. 2014 Jun;27(3):200-8. doi: 10.1089/jamp.2013.1037. Epub 2013 Aug 1.
Inhaled epithelial sodium channel (ENaC) blockers are designed to increase airway surface liquid volume, thereby benefiting cystic fibrosis patients. This study evaluated the safety, tolerability, and pharmacokinetics of multiple doses of ENaC blocker GS-9411, in healthy participants.
This randomized, double-blind, placebo-controlled, parallel-group, residential, Phase 1 study evaluated inhaled GS-9411 (2.4, 4.8, and 9.6 mg) or placebo, dosed twice daily for 14 days.
GS-9411 was well tolerated; 86.1% of treated participants completed dosing (n=31/36). Cough and dizziness (27.8% participants each; most of mild severity) were the most commonly reported adverse events and occurred in both placebo and GS-9411 treatment groups. Arrhythmias were not observed for GS-9411-treated participants, and electrocardiographic changes were not considered clinically significant. Serum potassium levels exceeded the upper limit of normal (>5 mmol/L), 4 hr after the morning dose in GS-9411 (n=16/24) and placebo (n=4/12) treatment groups (38 incidences total). Retesting revealed levels had returned to normal within 2-3 hr. In urine electrolyte analyses, obtained 0-6 hr after the Day 1 morning dose, mean sodium/potassium ratios significantly increased from values 0-6 hr before dosing. Increased urine sodium/potassium ratios corresponded with high urine concentrations of active GS-9411 metabolites, which inhibited sodium reabsorption in the kidney, leading to the observed transient hyperkalemia in these participants. Inhaled GS-9411 was well tolerated except for the emergence of transient clinically significant hyperkalemia; this finding resulted in termination of further clinical development of this drug and will necessitate development of a new generation of ENaC blockers, which provide a sustained improvement in mucociliary clearance, while reducing renal exposure to ENaC blockade. Transient increases in mean urine sodium/potassium ratios appeared to be the first signal of electrolyte imbalances resulting from drug-induced block of ENaC in the kidney. The results of this study strongly suggest that clinical trials of novel ENaC blockers will require intensive measurement of plasma and urine electrolyte levels.
吸入性上皮钠通道（ENaC）阻滞剂旨在增加气道表面液体量，从而使囊性纤维化患者受益。本研究评估了多剂量ENaC阻滞剂GS-9411在健康受试者中的安全性、耐受性和药代动力学。
这项随机、双盲、安慰剂对照、平行组、住院的1期研究评估了吸入性GS-9411（2.4、4.8和9.6毫克）或安慰剂，每日给药两次，共14天。
GS-9411耐受性良好；86.1%的受试参与者完成了给药（n=31/36）。咳嗽和头晕（各27.8%的参与者；大多数为轻度）是最常报告的不良事件，在安慰剂组和GS-9411治疗组中均有发生。接受GS-9411治疗的参与者未观察到心律失常，且心电图变化不被认为具有临床意义。GS-9411（n=16/24）和安慰剂（n=4/12）治疗组在晨服后4小时血清钾水平超过正常上限（>5 mmol/L）（共38例）。复测显示水平在2-3小时内恢复正常。在第1天晨服后0-6小时进行的尿电解质分析中，平均钠/钾比值较给药前0-6小时的值显著增加。尿钠/钾比值增加与活性GS-9411代谢物的高尿浓度相对应，这些代谢物抑制了肾脏中的钠重吸收，导致这些参与者出现观察到的短暂高钾血症。吸入性GS-9411耐受性良好，除了出现短暂的具有临床意义的高钾血症；这一发现导致该药物的进一步临床开发终止，并且有必要开发新一代的ENaC阻滞剂，其在改善黏液纤毛清除方面提供持续改善，同时减少肾脏对ENaC阻断的暴露。平均尿钠/钾比值的短暂增加似乎是肾脏中药物诱导的ENaC阻断导致电解质失衡的首个信号。本研究结果强烈表明，新型ENaC阻滞剂的临床试验将需要密集测量血浆和尿电解质水平。
