Pharmacokinetics of Fentanyl Sublingual Spray in Opioid-Naïve Participants: Results of a Phase 1, Multiple Ascending Dose Study

Abstract

Background and objectives: Fentanyl sublingual spray may be a viable alternative to intravenous (IV) opioids for the treatment of acute pain. As patients with acute pain may include those who have limited prior exposure to opioids, this phase 1, open-label, randomized, multiple ascending-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple doses of fentanyl sublingual spray in opioid-naïve participants. This article primarily reports the pharmacokinetics results.

Methods: Study drugs were administered in four dosing cohorts: every 0.5, 1, 2, or 4 h for a maximum of three doses per cohort. Eight fasted individuals per cohort were randomized to either fentanyl sublingual spray (100, 200, or 400 µg) or fentanyl citrate IV 50 µg (6:2 ratio). Blood samples were collected pre-dose through 24 h post first dose.

Results: A total of 98 healthy adults were enrolled and 96 completed the study. Mean plasma fentanyl concentrations increased with increasing doses of fentanyl sublingual spray administered every 0.5-4 h. With multiple doses, systemic exposure increased relative to the first dose; shorter dosing intervals resulted in higher concentrations. Analysis of dose proportionality suggested that systemic exposure increased in a linear but slightly greater than dose-proportional manner. Accumulation between the first and last doses of fentanyl sublingual spray was more pronounced with shorter dosing intervals.

Conclusion: Dose-dependent fentanyl pharmacokinetics following multiple doses of fentanyl sublingual spray were well characterized in an opioid-naïve population. CLINICALTRIALS.

Gov identifier: NCT02641340.

Conflict of interest statement

Conflict of interest

RR reports serving as a consultant or advisory board member or receiving research funding from the Alfred Mann Foundation, Archimedes, BioDelivery Sciences International, Inc., Insys Development Company, 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, JY, and SJ are employees of and hold stock in Insys Development Company, Inc. CK is an employee of Lotus Clinical Research, LLC, which received grants for conducting clinical investigations in connection with this trial. NS is owner and founder of Lotus Clinical Research, LLC, which received grants for conducting clinical investigations in connection with this trial; reports receiving research funding from Acacia Pharma Ltd, AcelRx Pharmaceuticals, Inc., Alkermes, Inc., AMAG Pharmaceuticals, Inc., Aponia Laboratories, Inc., Astellas Pharma B.V., AstraZeneca L.P., Auxilium Pharmaceuticals, Inc., Biogen Idec MA Inc., Biom’Up, Bonti, Inc., Braeburn Pharmaceuticals, Inc., Cadence Pharmaceuticals, Inc., Cephalon, Inc., Charleston Laboratories, Inc., Chromocell Corporation, Collegium Pharmaceutical, Inc., Columbia Laboratories, Inc., Coronado Biosciences, Cubist Pharmaceuticals, Inc., Durect Corporation, Frazier Management, LLC, Grace Therapeutics LLC, Grifols, Inc., Heron Therapeutics, Inc., IMMPACT, Imprimis Pharmaceuticals, Inc., Innocoll Pharmaceuticals, Insys Therapeutics, Inc., iX Biopharma Ltd., KemPharm, Inc., KLSMC Stem Cells, Inc., Kowa Research Institute, Inc., Mallinckrodt Inc., a Covidien company, MedRx USA, Inc., Merck Sharp & Dohme Corp., Mira Pharma, Inc., Myoscience, Inc., Naurex, Inc., an affiliate of Allergan Sales, LLC, Nektar Therapeutics, Novartis Consumer Health, Inc., Novartis Pharmaceuticals Corporation, Pacira Pharmaceuticals, Inc., Pfizer, Inc., PPD Development, LLC, ProFibrix, Inc., Purdue Pharma L.P., QRxPharma, Inc., Recro Pharma, Inc., Regenesis Biomedical Inc., Revogenex, SAI MedPartners LLC, Shionogi Inc., Teva Pharmaceuticals USA, Trevena, Inc., Vertex Pharmaceuticals, Inc., VM Pharma LLC., WEX Pharmaceuticals, Inc. SN reports receiving research grants from Covidien and Endo Pharmaceuticals Inc.; serving on the speakers’ bureau for Archimedes, Covidien, Eli Lilly and Company, Johnson & Johnson, ProStrakan, and Teva Pharmaceuticals; and serving as a consultant for Depomed, Galena, Insys Development Company, Inc., Teva Pharmaceuticals, and Zogenix, Inc.

Ethics approval

All procedures in this study were in accordance with the 1964 Helsinki declaration (and its amendments). A valid Institutional Review Board (IRB) reviewed and approved the protocol before study initiation.

Informed consent

Written informed consent was obtained prior to study participation.

Figures

Fig. 1

Mean fentanyl concentration-time profiles after administration of a fentanyl sublingual spray 100 µg, b fentanyl sublingual spray 200 µg, c fentanyl sublingual spray 400 µg, or d fentanyl citrate IV 50 µg. Cohort 1, every 4 h; Cohort 2, every 2 h; Cohort 3, every 1 h; Cohort 4, every 0.5 h

Fig. 2

Dose proportionality of fentanyl aCmaxn, b AUC0–inf, and c AUC0–t after administration of fentanyl sublingual spray 100 µg (Cycle 1), 200 µg (Cycle 2), and 400 µg (Cycle 3) every 4 h (Cohort 1), 2 h (Cohort 2), 1 h (Cohort 3), or 0.5 h (Cohort 4). AUC0–t area under the plasma concentration–time curve from time–zero to the time of the last quantifiable concentration, calculated using the linear-log trapezoidal rule, AUC0–inf area under the plasma concentration–time curve from time–zero extrapolated to infinity, calculated using the linear-log trapezoidal rule, Cmaxn maximum plasma concentrations after last dose