Ottoboni Tom, Keller Mary Rose, Cravets Matt, Clendeninn Neil, Quart Barry
Pharmaceutical and Translational Sciences, Heron Therapeutics, Inc., San Diego, CA, USA.
Clinical Operations, Heron Therapeutics, Inc., San Diego, CA, USA.
Drug Des Devel Ther. 2018 Mar 1;12:429-435. doi: 10.2147/DDDT.S155875. eCollection 2018.
Fosaprepitant, an intravenous (IV) aprepitant prodrug for chemotherapy-induced nausea and vomiting prophylaxis, is associated with systemic and infusion-site reactions attributed in part to its surfactant, polysorbate 80. HTX-019 is an IV aprepitant formulation free of polysorbate 80 and other synthetic surfactants.
This open-label, single-dose, randomized, two-way crossover bioequivalence study compared pharmacokinetics and safety of HTX-019 and fosaprepitant. Healthy subjects received single-dose HTX-019 (130 mg) or fosaprepitant (150 mg) IV over 30 min, with ≥7-day washout between doses. Blood samples were evaluated for pharmacokinetics and bioequivalence; safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. Ninety-seven of one hundred enrolled subjects completed the study.
Baseline characteristics were comparable between treatment sequences. For HTX-019, mean (percent coefficient of variation) area under the curve (AUC) from time 0 to time of last measurable plasma concentration (AUC), AUC from time 0 to infinity (AUC), and plasma concentration at 12 h (C) for HTX-019 were 43,729 hng/mL (32.7), 45,460 hng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 hng/mL (32.0), 46,163 hng/mL (36.6), and 1,022 ng/mL (28.5). Also, 90% CIs (94.186-101.354) were within bioequivalence bounds (80%-125%). Within 1 h following infusion start, one (1%) HTX-019 recipient reported one TEAE, while 20 (20%) fosaprepitant recipients reported 32 TEAEs. Dyspnea occurred in three fosaprepitant recipients (at <1 min in two subjects and at 18 min in one subject, considered study drug related) and one HTX-019 recipient (at 120 h, associated with a respiratory tract infection and considered not related to the study drug). No severe TEAEs, serious adverse events, or deaths occurred; all TEAEs resolved.
HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis.
福沙匹坦是一种用于预防化疗引起的恶心和呕吐的静脉注射（IV）阿瑞匹坦前体药物，其全身和输注部位反应部分归因于其表面活性剂聚山梨酯80。HTX-019是一种不含聚山梨酯80和其他合成表面活性剂的静脉注射阿瑞匹坦制剂。
这项开放标签、单剂量、随机、双向交叉生物等效性研究比较了HTX-019和福沙匹坦的药代动力学和安全性。健康受试者在30分钟内静脉注射单剂量HTX-019（130毫克）或福沙匹坦（150毫克），两次给药之间的洗脱期≥7天。对血样进行药代动力学和生物等效性评估；安全性评估包括治疗中出现的不良事件（TEAE）和严重不良事件。100名入组受试者中有97名完成了研究。
各治疗序列之间的基线特征具有可比性。对于HTX-019，从时间0到最后可测量血浆浓度的曲线下面积（AUC）、从时间0到无穷大的AUC以及12小时时的血浆浓度（C）的平均值（变异系数百分比）分别为43,729小时纳克/毫升（32.7）、45,460小时纳克/毫升（36.8）和988.4纳克/毫升（27.5）；福沙匹坦的相应值分别为44,130小时纳克/毫升（32.0）、46,163小时纳克/毫升（36.6）和1,022纳克/毫升（28.5）。此外，90%置信区间（94.186 - 101.354）在生物等效性界限（80% - 125%）内。在开始输注后1小时内，1名（1%）HTX-019受试者报告了1例TEAE，而20名（20%）福沙匹坦受试者报告了32例TEAE。三名福沙匹坦受试者出现呼吸困难（两名受试者在<1分钟时出现，一名受试者在18分钟时出现，被认为与研究药物有关），一名HTX-019受试者出现呼吸困难（在120小时时出现，与呼吸道感染有关，被认为与研究药物无关）。未发生严重TEAE、严重不良事件或死亡；所有TEAE均得到缓解。
HTX-019与福沙匹坦生物等效，对于预防化疗引起的恶心和呕吐，可能是福沙匹坦的一种更安全的替代药物。
