Abstract：
BACKGROUND: Nasal congestion could affect the absorption of an epinephrine nasal spray (ENS).
OBJECTIVE: To compare the pharmacokinetics of 13.2 mg ENS with nasal congestion vs without congestion and vs intramuscular (IM) treatments.
METHODS: This phase I, open-label, 4-period randomized crossover study enrolled 51 healthy adults with seasonal allergies into cohorts that received a single dose of 13.2 mg ENS (NDS1C; Bryn Pharma, Lebanon, New Jersey) administered as 2 consecutive sprays in either opposite nostrils (cohort 1) or the same nostril (cohort 2). Both cohorts received 13.2 mg ENS with and without nasal allergen challenge (NAC), 0.3 mg IM epinephrine by autoinjector, and 0.5 mg IM epinephrine by manual syringe (MS).
RESULTS: The ENS after NAC resulted in higher extent and peak exposures and more rapid time to maximum plasma concentration vs ENS without NAC and IM treatments. In cohort 1, the maximum observed baseline-adjusted epinephrine plasma concentration (pg/mL) of ENS with NAC, IM autoinjector, IM MS, or ENS without NAC was 458.0, 279.0, 364.2, and 270.1, respectively, and in cohort 2 was 436.3, 228.2, 322.3, and 250.8, respectively. The maximum observed baseline-adjusted epinephrine plasma concentration geometric mean ratio (90% CI) for ENS with NAC vs without NAC in cohort 1 was 170% (123%-234%), and in cohort 2 was 174% (115%-263%). In cohort 1, the time to maximum plasma concentration was 15, 21, 45, and 25 minutes, respectively, and in cohort 2 was 18, 20, 45, and 20 minutes, respectively (P < .01 for ENS with NAC vs IM MS). The postdose mean heart rate and blood pressure remained stable and relatively similar to predose values regardless of plasma epinephrine concentration. Mild nausea and headache were the most common adverse events with ENS.
CONCLUSIONS: The 13.2 mg ENS with congestion exhibited enhanced absorption vs IM treatments and ENS without congestion and seemed to be well tolerated. There was no clinically impactful relationship between pharmacodynamic effects and plasma epinephrine concentration.
OBJECTIVE: To compare the pharmacokinetics of 13.2 mg ENS with nasal congestion vs without congestion and vs intramuscular (IM) treatments.
METHODS: This phase I, open-label, 4-period randomized crossover study enrolled 51 healthy adults with seasonal allergies into cohorts that received a single dose of 13.2 mg ENS (NDS1C; Bryn Pharma, Lebanon, New Jersey) administered as 2 consecutive sprays in either opposite nostrils (cohort 1) or the same nostril (cohort 2). Both cohorts received 13.2 mg ENS with and without nasal allergen challenge (NAC), 0.3 mg IM epinephrine by autoinjector, and 0.5 mg IM epinephrine by manual syringe (MS).
RESULTS: The ENS after NAC resulted in higher extent and peak exposures and more rapid time to maximum plasma concentration vs ENS without NAC and IM treatments. In cohort 1, the maximum observed baseline-adjusted epinephrine plasma concentration (pg/mL) of ENS with NAC, IM autoinjector, IM MS, or ENS without NAC was 458.0, 279.0, 364.2, and 270.1, respectively, and in cohort 2 was 436.3, 228.2, 322.3, and 250.8, respectively. The maximum observed baseline-adjusted epinephrine plasma concentration geometric mean ratio (90% CI) for ENS with NAC vs without NAC in cohort 1 was 170% (123%-234%), and in cohort 2 was 174% (115%-263%). In cohort 1, the time to maximum plasma concentration was 15, 21, 45, and 25 minutes, respectively, and in cohort 2 was 18, 20, 45, and 20 minutes, respectively (P < .01 for ENS with NAC vs IM MS). The postdose mean heart rate and blood pressure remained stable and relatively similar to predose values regardless of plasma epinephrine concentration. Mild nausea and headache were the most common adverse events with ENS.
CONCLUSIONS: The 13.2 mg ENS with congestion exhibited enhanced absorption vs IM treatments and ENS without congestion and seemed to be well tolerated. There was no clinically impactful relationship between pharmacodynamic effects and plasma epinephrine concentration.
摘要：
背景：鼻腔充血可能影响肾上腺素鼻腔喷雾剂（ENS）的吸收。
目的：比较13.2mgENS鼻塞与无充血和肌内（IM）治疗的药代动力学。
方法：第一阶段，开放标签，4期随机交叉研究将51名具有季节性过敏的健康成年人纳入队列，这些队列接受了单次剂量的13.2mgENS（NDS1C），在相对的鼻孔（队列1）或相同的鼻孔（队列2）中连续两次喷雾。两组均接受了13.2mgENS，有和没有鼻过敏原攻击（NAC），通过自动注射器0.3mgIM肾上腺素，和0.5mgIM肾上腺素通过手动注射器（MS）。
结果：与没有NAC和IM治疗的ENS相比，NAC后的ENS导致更高的程度和峰值暴露以及更快的达到最大血浆浓度（Tmax）的时间。在队列1中，观察到的基线调整的肾上腺素血浆浓度最大值（Cmax，pg/mL)与带有NAC的ENS，IM自动注射器,IMMS,或没有NAC的ENS分别为458.0、279.0、364.2和270.1，队列2中分别为436.3、228.2、322.3和250.8。队列1中具有NAC的ENS与不具有NAC的ENS的Cmax几何平均比（90％CI）为170％（123％，234%)，在队列2中为174%(115%，263%）。在队列1中，Tmax为15、21、45和25分钟，分别,队列2是18、20、45和20分钟，分别（对于使用NAC和IMMS的ENS，p<0.01）。无论血浆肾上腺素浓度如何，给药后平均心率和血压保持稳定，并且与给药前值相对相似。轻度恶心和头痛是ENS最常见的不良事件。
结论：13.2mg有充血的ENS与IM治疗和无充血的ENS相比显示出增强的吸收，并且表现出良好的耐受性。药效学作用与血浆肾上腺素浓度之间没有临床影响的关系。
目的：比较13.2mgENS鼻塞与无充血和肌内（IM）治疗的药代动力学。
方法：第一阶段，开放标签，4期随机交叉研究将51名具有季节性过敏的健康成年人纳入队列，这些队列接受了单次剂量的13.2mgENS（NDS1C），在相对的鼻孔（队列1）或相同的鼻孔（队列2）中连续两次喷雾。两组均接受了13.2mgENS，有和没有鼻过敏原攻击（NAC），通过自动注射器0.3mgIM肾上腺素，和0.5mgIM肾上腺素通过手动注射器（MS）。
结果：与没有NAC和IM治疗的ENS相比，NAC后的ENS导致更高的程度和峰值暴露以及更快的达到最大血浆浓度（Tmax）的时间。在队列1中，观察到的基线调整的肾上腺素血浆浓度最大值（Cmax，pg/mL)与带有NAC的ENS，IM自动注射器,IMMS,或没有NAC的ENS分别为458.0、279.0、364.2和270.1，队列2中分别为436.3、228.2、322.3和250.8。队列1中具有NAC的ENS与不具有NAC的ENS的Cmax几何平均比（90％CI）为170％（123％，234%)，在队列2中为174%(115%，263%）。在队列1中，Tmax为15、21、45和25分钟，分别,队列2是18、20、45和20分钟，分别（对于使用NAC和IMMS的ENS，p<0.01）。无论血浆肾上腺素浓度如何，给药后平均心率和血压保持稳定，并且与给药前值相对相似。轻度恶心和头痛是ENS最常见的不良事件。
结论：13.2mg有充血的ENS与IM治疗和无充血的ENS相比显示出增强的吸收，并且表现出良好的耐受性。药效学作用与血浆肾上腺素浓度之间没有临床影响的关系。
