Pharmacokinetics of 800 mcg of sublingual fentanyl tablets, administered as one 800-mcg tablet, two 400-mcg tablets, or four 200-mcg tablets, in healthy volunteers

Abstract

Sublingual fentanyl tablet (Abstral®) is a rapid-onset formulation under evaluation in the United States and approved in Europe for management of breakthrough pain in opioid-tolerant patients with cancer. Understanding whether multiple lower-dose tablets yield the same pharmacokinetics as a single tablet containing an equivalent total dose may aid physicians and be more convenient for patients, particularly during dose titration. This open-label, randomized, single-dose, 3-period crossover study compared bioavailability of sublingual fentanyl 800 mcg administered as one 800-mcg tablet, two 400-mcg tablets, or four 200-mcg tablets, administered by placing on the floor of the mouth directly under the tongue until completely dissolved. In total, 36 patients (mean age, 27.3 y; 53% female; 83% white) were randomized into 6 dosing sequences, with 7 days between doses. Naltrexone 50 mg tablets were administered concomitantly to reduce potential for respiratory-related adverse events (AEs). Blood samples for pharmacokinetic assessments were taken predose through 30 hours postdose. Rate and extent of exposure of sublingual fentanyl administered as two 400-mcg tablets and four 200-mcg tablets, measured by mean Cmax, AUC(0-t), and AUC(0-∞), were 98-112% and 97-113%, respectively, of the corresponding measures for one 800-mcg tablet. Tmax and t½ were similar between treatments. These data indicate bioequivalence of sublingual fentanyl administered as one 800-mcg tablet, two 400-mcg tablets, and four 200-mcg tablets. All doses were generally well tolerated. AEs occurred in 21% (7/33), 28% (9/32), and 24% (2/33) of subjects receiving the single 800-mcg tablet, two 400-mcg tablets, and four 200-mcg tablets, respectively. The most common AEs included nausea, vomiting, dizziness, headache, fatigue, and myalgia. Due to dose-proportional pharmacokinetics, multiple lower-dose sublingual fentanyl tablets can be administered to achieve the same effects as a smaller number of larger-dose tablets. Editorial and writing support was provided by Synchrony Medical LLC, funded by ProStrakan Group.