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 Quart5 1Pharmaceutical and Translational Sciences, Heron Therapeutics, Inc., San Diego, CA, USA; 2Clinical Operations, Heron Therapeutics, Inc., San Diego, CA, USA; 3Biometrics, Heron Therapeutics, Inc., San Diego, CA, USA; 4C...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2018-03-01
|
| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/bioequivalence-of-htx-019-aprepitant-iv-and-fosaprepitant-in-healthy-s-peer-reviewed-article-DDDT |
| _version_ | 1818544992674643968 |
|---|---|
| author | Ottoboni T Keller MR Cravets M Clendeninn N Quart B |
| author_facet | Ottoboni T Keller MR Cravets M Clendeninn N Quart B |
| author_sort | Ottoboni T |
| collection | DOAJ |
| description | Tom Ottoboni,1 Mary Rose Keller,2 Matt Cravets,3 Neil Clendeninn,4 Barry Quart5 1Pharmaceutical and Translational Sciences, Heron Therapeutics, Inc., San Diego, CA, USA; 2Clinical Operations, Heron Therapeutics, Inc., San Diego, CA, USA; 3Biometrics, Heron Therapeutics, Inc., San Diego, CA, USA; 4Clinical, Heron Therapeutics, Inc., San Diego, CA, USA; 5Heron Therapeutics, Inc., San Diego, CA, USA 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 |
| first_indexed | 2024-12-11T22:55:42Z |
| format | Article |
| id | doaj.art-b5041552aba5406cabf4e078f90f8336 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-11T22:55:42Z |
| publishDate | 2018-03-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-b5041552aba5406cabf4e078f90f83362022-12-22T00:47:15ZengDove Medical PressDrug Design, Development and Therapy1177-88812018-03-01Volume 1242943536997Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluationOttoboni TKeller MRCravets MClendeninn NQuart BTom Ottoboni,1 Mary Rose Keller,2 Matt Cravets,3 Neil Clendeninn,4 Barry Quart5 1Pharmaceutical and Translational Sciences, Heron Therapeutics, Inc., San Diego, CA, USA; 2Clinical Operations, Heron Therapeutics, Inc., San Diego, CA, USA; 3Biometrics, Heron Therapeutics, Inc., San Diego, CA, USA; 4Clinical, Heron Therapeutics, Inc., San Diego, CA, USA; 5Heron Therapeutics, Inc., San Diego, CA, USA 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, surfactanthttps://www.dovepress.com/bioequivalence-of-htx-019-aprepitant-iv-and-fosaprepitant-in-healthy-s-peer-reviewed-article-DDDTantiemeticspolysorbate 80safetysurfactant |
| spellingShingle | Ottoboni T Keller MR Cravets M Clendeninn N Quart B Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation Drug Design, Development and Therapy antiemetics polysorbate 80 safety surfactant |
| title | Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation |
| title_full | Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation |
| title_fullStr | Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation |
| title_full_unstemmed | Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation |
| title_short | Bioequivalence of HTX-019 (aprepitant IV) and fosaprepitant in healthy subjects: a Phase I, open-label, randomized, two-way crossover evaluation |
| title_sort | bioequivalence of htx 019 aprepitant iv and fosaprepitant in healthy subjects a phase i open label randomized two way crossover evaluation |
| topic | antiemetics polysorbate 80 safety surfactant |
| url | https://www.dovepress.com/bioequivalence-of-htx-019-aprepitant-iv-and-fosaprepitant-in-healthy-s-peer-reviewed-article-DDDT |
| work_keys_str_mv | AT ottobonit bioequivalenceofhtx019aprepitantivandfosaprepitantinhealthysubjectsaphaseiopenlabelrandomizedtwowaycrossoverevaluation AT kellermr bioequivalenceofhtx019aprepitantivandfosaprepitantinhealthysubjectsaphaseiopenlabelrandomizedtwowaycrossoverevaluation AT cravetsm bioequivalenceofhtx019aprepitantivandfosaprepitantinhealthysubjectsaphaseiopenlabelrandomizedtwowaycrossoverevaluation AT clendeninnn bioequivalenceofhtx019aprepitantivandfosaprepitantinhealthysubjectsaphaseiopenlabelrandomizedtwowaycrossoverevaluation AT quartb bioequivalenceofhtx019aprepitantivandfosaprepitantinhealthysubjectsaphaseiopenlabelrandomizedtwowaycrossoverevaluation |