Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers

Abstract

Objective: Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants.

Research design: Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7.

Results: Fifty participants (19−53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27–0.60 h post-dose for fentanyl sublingual spray. Peak (C_max) and total (AUC_0–t, AUC_0–∞) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses.

Conclusions: Overall, single-dose fentanyl sublingual spray (100–800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses between 400–800 mcg may be administered in settings with nasal cannula oxygenation.

Keywords:

• Fentanyl
• sublingual spray
• opioids

Transparency

Declaration of funding

This study was supported by INSYS Development Company, Inc.

Declaration of financial/other relationships

RR reports serving as a consultant or advisory board member or receiving research funding from the Alfred Mann Foundation, Archimedes Pharma, BioDelivery Sciences International, Inc., Jazz Pharmaceuticals, Meda, Medasys, Inc., and Medtronic, Inc.; serving on the speakers’ bureau for Jazz Pharmaceuticals; and receiving research funding from Alfred Mann Foundation, Bioness, Boston Scientific, Collegium Pharmaceuticals, CNS Therapeutics, Jazz Pharmaceuticals, Medtronic, Inc., Myoscience, NeurAxon, Inc., Spinal Modulation, Spinal Restoration, and St. Jude Medical. DAO, NP, and JY are employees of and hold stock in INSYS Development Company, Inc. CK is an employee of and NS is owner and founder of Lotus Clinical Research, LLC, which received grants for conducting clinical investigations in connection with this trial. SN reports serving as a consultant or speaker or receiving research grants from AstraZeneca, Archimedes Pharma, BioDelivery Sciences International, Collegium Pharmaceuticals, Covidien, Depomed, Daiichi Sankyo, Inc., Egalet, Endo Pharmaceuticals Inc., Galena Biopharma, Inc., INSYS Development Company, Inc., Shionogi, Inc., Pernix Therapeutics, Purdue Pharma, Salix Pharmaceuticals, Sentynl Therapeutics, Inc., and Teva Pharmaceuticals. SV is a former employee of INSYS Development Company, Inc.

Acknowledgments

Technical editorial and medical writing support, under the guidance of the authors, was provided by Christina Cognata Smith, PharmD, MBA, formerly an employee of INSYS Development Company, Inc. Funding for this support was provided by INSYS Development Company, Inc., Chandler, AZ. ClinicalTrials.gov Identifier: NCT02576353.