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Clinical Trial
. 2018 Mar 1:12:429-435.
doi: 10.2147/DDDT.S155875. eCollection 2018.

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

Tom Ottoboni  1 , Mary Rose Keller  2 , Matt Cravets  3 , Neil Clendeninn  4 , Barry Quart  5
Affiliations
Clinical Trial

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

Tom Ottoboni et al. Drug Des Devel Ther. .

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 (AUC0-t), AUC from time 0 to infinity (AUC0-inf), and plasma concentration at 12 h (C12 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.

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Conflict of interest statement

Disclosure TO, MRK, MC, NC, and BQ are Heron Therapeutics, Inc., employees and report stock ownership. TO, NC, and BQ report leadership roles with Heron Therapeutics, Inc. TO reports travel, accommodation, and expenses reimbursed by Heron Therapeutics, Inc. The authors report no other conflicts of interest in this work.

Figures

Figure 1
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
Figure 2
Mean fosaprepitant plasma concentration–time curve (pharmacokinetics population). Abbreviation: IV, intravenous.
Figure 3
Figure 3
Mean aprepitant plasma concentration–time curves for HTX-019 and fosaprepitant (pharmacokinetics population). Abbreviation: IV, intravenous.
See this image and copyright information in PMC

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