Dose Proportionality and Pharmacokinetics of Fentanyl Buccal Soluble Film in Healthy Subjects
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Background and Objectives: Fentanyl buccal soluble film (FBSF) is a small, bilayered, water-soluble polymer film (BioErodible MucoAdhesive; BEMA™) that adheres to the buccal mucosa and rapidly delivers fentanyl into the systemic circulation. It is approved for the treatment of cancer breakthrough pain in adult opioid-tolerant patients. The objective of this study was to evaluate the dose proportionality of the pharmacokinetics of FBSF in healthy subjects across a range of doses.
Methods: This was a phase I, open-label, single-dose, three-period, Latin-square crossover study in which 12 healthy subjects received single FBSF doses of 200, 600 and 1200 μg with 72 hours between doses. Oral naltrexone was administered to each subject prior to and after each study dose. Serial venous blood samples were collected for 48 hours after study drug administration. Adverse events were recorded throughout the study. Dose linearity was examined using a power model (P=a×Doseb), where P represents the dependent variable (maximum plasma drug concentration [Cmax], area under the plasma concentration-time curve [AUC] from time zero to time of the last measurable concentration [AUClast], or AUC from time zero to infinity [AUC∞]), and a and b are constants. A value of b ≈ 1 indicated linearity.
Results: Following administration of FBSF doses of 200–1200 μg, mean Cmax values increased in a linear manner with values ranging from 0.383 ng/mL to 2.19ng/mL, respectively. Mean AUClast values increased from 3.001 ng ·/mL to 19.17 ng·h/mL and mean AUC∞ increased in a linear manner from 3.456 ng·h/mL to 20.43 ng ·h/mL. All reported adverse events were considered to be mild to moderate in severity.
Conclusions: This study demonstrates that peak fentanyl plasma concentrations and overall exposure increase in a dose-proportional manner following administration of FBSF.
KeywordsFentanyl Naltrexone Buccal Mucosa Dose Proportionality Oxyhaemoglobin Saturation
The authors thank MK Grandison, PhD, Nila Bhana, MSc, and Alan J. Klopp, PhD, of inScience Communications, a Wolters Kluwer business, for providing medical writing support funded by Meda Pharmaceuticals, Inc.
Andrew L. Finn, PharmD, and Niraj Vasisht, PhD, are employees and shareholders of BioDelivery Sciences International, Inc., the developer of FBSF. Drs Finn and Vasisht are also cited as inventors on the FBSF patent applications. Jeffrey G. Stark, PhD, is an employee of Worldwide Clinical Trials Drug Development Solutions (formerly CEDRA Corporation), the research facility that conducted the study. Larry N. Gever, PharmD, is the Director of Medical Affairs at Meda Pharmaceuticals, Inc., the company that is marketing FBSF. Ignacio Tagarro, PhD, is an employee of Meda Pharmaceuticals, Inc.
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