Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation

Abstract

Introduction: 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.

Materials and methods: 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.

Results: 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_0-t), AUC from time 0 to infinity (AUC_0-inf), and plasma concentration at 12 h (C_{12 h}) for HTX-019 were 43,729 h*ng/mL (32.7), 45,460 h*ng/mL (36.8), and 988.4 ng/mL (27.5), respectively; corresponding fosaprepitant values were 44,130 h*ng/mL (32.0), 46,163 h*ng/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.

Conclusion: HTX-019 was bioequivalent to fosaprepitant and may provide a safer alternative to fosaprepitant for chemotherapy-induced nausea and vomiting prophylaxis.

Keywords: antiemetics; polysorbate 80; safety; surfactant.

Figure 1

Study design. Notes: Confinement lasted from the morning of day –1 through day 4 of each treatment period (through the pharmacokinetic collection at 72 h on day 4), for a total of ~5 days per treatment period. ^aObservation period duration was 72 h for each treatment period. Abbreviation: IV, intravenous.

Figure 2

Mean fosaprepitant plasma concentration–time curve (pharmacokinetics population). Abbreviation: IV, intravenous.

Figure 3

Mean aprepitant plasma concentration–time curves for HTX-019 and fosaprepitant (pharmacokinetics population). Abbreviation: IV, intravenous.