Heron Therapeutics, Inc., 4242 Campus Point Court, Suite 200, San Diego, CA 92121, USA.
Future Oncol. 2019 Mar;15(8):865-874. doi: 10.2217/fon-2018-0809. Epub 2018 Dec 21.
HTX-019 (CINVANTI [aprepitant injectable emulsion]) is a neurokinin 1 receptor antagonist approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 is free of polysorbate 80 and other synthetic surfactants and showed bioequivalence to and a more favorable safety profile than fosaprepitant when administered as a 30-min infusion in healthy subjects. The shortage of small-volume parenteral solutions led to a recommendation to administer HTX-019 by intravenous push. The objectives were to evaluate pharmacokinetics, tolerability and safety following HTX-019 administration by injection versus infusion.
MATERIALS & METHODS: Study comprised Part A, a pilot Phase I, single-center, randomized, pharmacokinetic, safety and tolerability, open-label study, followed by Part B, a two-sequence crossover study of HTX-019 130 mg in healthy adults, via injection and infusion. Blood samples were evaluated for aprepitant pharmacokinetics and bioequivalence. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory testing and electrocardiograms.
In Part A, 24 subjects were randomly assigned to three cohorts (n = 8 per cohort) and received HTX-019 130 mg, administered intravenously over 15 min (cohort 1), 5 min (cohort 2) or 2 min (cohort 3). Progression to Part B occurred after acceptable tolerability was established in cohorts 2 and 3. In Part B, 50 randomized subjects received a 2-min injection (9 ml/min) and 30-min infusion (296 ml/h) of HTX-019 130 mg. Bioequivalence was demonstrated for HTX-019 injection and infusion. Both administration methods via a peripheral line were well tolerated; eight subjects experienced 11 TEAEs (six related) following injection and nine experienced 14 TEAEs (nine related) following infusion. Headache and fatigue were the most prevalent treatment-related TEAEs; one subject per group experienced feeling hot ≤30 min after drug administration.
Pharmacokinetic and tolerability profiles of 2-min HTX-019 injection support this potential alternative administration method for CINV prevention.
HTX-019（CINVANTI [阿瑞匹坦注射液]）是一种神经激肽 1 受体拮抗剂，用于预防急性和延迟性化疗引起的恶心和呕吐（CINV）。HTX-019不含聚山梨酯 80 和其他合成表面活性剂，与福沙匹坦相比，在健康受试者中以 30 分钟输注时具有生物等效性和更有利的安全性。由于小容量的肠外溶液短缺，建议通过静脉推注给予 HTX-019。目的是评估 HTX-019 注射与输注给药后的药代动力学、耐受性和安全性。
研究包括部分 A，一项单中心、随机、开放标签、单剂量、Ⅰ期探索性研究，随后是部分 B，一项健康成年人 HTX-019 130mg 注射与输注的两序列交叉研究。评估了阿瑞匹坦的药代动力学和生物等效性。安全性评估包括治疗后出现的不良事件（TEAE）、生命体征、临床实验室检测和心电图。
在部分 A 中，24 名受试者被随机分为三组（每组 8 名），并接受 HTX-019 130mg，静脉输注 15 分钟（第 1 组）、5 分钟（第 2 组）或 2 分钟（第 3 组）。在第 2 组和第 3 组接受后，可接受的耐受性建立后，进展到部分 B。在部分 B 中，50 名随机受试者接受 HTX-019 130mg 2 分钟注射（9ml/min）和 30 分钟输注（296ml/h）。HTX-019 注射和输注具有生物等效性。两种外周通路给药方法均具有良好的耐受性；8 名受试者在注射后出现 11 例 TEAEs（6 例相关），9 名受试者在输注后出现 14 例 TEAEs（9 例相关）。头痛和疲劳是最常见的治疗相关 TEAEs；每组各有 1 名受试者在药物给药后≤30 分钟感觉发热。
2 分钟 HTX-019 注射的药代动力学和耐受性特征支持这种预防 CINV 的潜在替代给药方法。
