Title:
Pharmacokinetics and dose proportionality of fentanyl sublingual spray: a single-dose 5-way crossover study.

Abstract:
Fentanyl sublingual spray is a novel formulation of fentanyl for sublingual delivery that was designed to enhance the rate and extent of absorption of fentanyl for management of breakthrough cancer pain (BTCP).
The primary objective of this study was to determine the pharmacokinetics and dose proportionality of 5 different doses (100, 200, 400, 600, and 800 μg) of fentanyl sublingual spray in healthy subjects under fasted conditions (part A); the secondary objective was to assess the effects of temperature and pH in the oral cavity on relative bioavailability of fentanyl (part B).
Analyses were performed on venous blood samples drawn 5 min to 36 h after administration of fentanyl sublingual spray (Subsys(®), Insys Therapeutics, Inc., Chandler, AZ, USA). Part A of this phase I study was a 5-treatment, 5-sequence, 5-period crossover study in which subjects received a single treatment of each of the 5 fentanyl sublingual spray doses. Dose proportionality was assessed using analysis of variance and linear regression techniques. Part B was a 5-treatment, 2-sequence, 5-period crossover study in which subjects received a single assigned dose of fentanyl sublingual spray 200 μg under the following 5 conditions: no pretreatment, pretreatment with cold or hot beverage, and pretreatment with low- or high-pH beverage. Naltrexone was administered to block potential opioid effects associated with fentanyl. Adverse events (AEs) were monitored and recorded throughout the study.
Fifty-three subjects (15 men, 38 women; mean age, 31 years) were enrolled in part A. Fourteen subjects (11 men, 3 women; mean age, 32 years) were enrolled in part B. The first quantifiable mean plasma concentrations of fentanyl were observed at the first sample time (5 min) for all doses. Mean maximum plasma concentration (C(max)) increased with increases in dose, whereas median time to reach C max (t max) tended to decrease with increases in dose. The dose-normalized C(max), area under the plasma concentration-time curve from time zero to infinity (AUC∞), and AUC from time zero to time of last measurable concentration (AUClast) values were linear and consistent with dose proportionality across the 100-800 μg dose range. Pretreatment of the oral cavity with a cold or hot beverage, or low- or high-pH beverage, did not appreciably alter fentanyl absorption (C(max) and AUC∞ values). The most commonly reported AEs were nausea and vomiting.
In healthy subjects, administration of fentanyl sublingual spray produced a rapid rise in fentanyl plasma concentrations. Dose-dependent parameters (C max and AUC) showed dose proportionality across the range of 100-800 μg. Altering the local environment of the oral cavity (temperature and pH) showed no effects on the bioavailability of fentanyl. The rapid and predictable rise in plasma fentanyl concentrations following administration of fentanyl sublingual spray corresponds with the rapid onset and duration of many BTCP episodes.