Bioavailability of two oral fentanyl transmucosal formulations in healthy volunteers: an open-label, crossover, randomised study.

Abstract

Introduction: Oral transmucosal fentanyl citrate (OTFC) was the first product specifically designed for the treatment of breakthrough pain. It is formulated as a sweetened lozenge on a plastic handle (stick) and it is self-administered by the patient, allowing the modulability or flexibility in dosing. Objectives: To prove bioequivalence of a test (T) OTFC product compared to the reference (R) formulation. Material and methods: Open-label, crossover, randomized, single-dose bioequivalence study in healthy volunteers, with two study periods and two sequences, with a washout period of at least 10 days. On each study day, subjects received 400 μg of fentanyl. They were instructed to rub the tablet gently against the buccal mucosa and not to suck on or chew it, and the investigators controlled each administration to ensure that it was consumed during 15 minutes. Given the high pharmacokinetic variability, a two-stage design was established and bioequivalence decision was based on 94.12% confidence intervals of Cmax and AUC0-t geometric means ratio. Results: 36 subjects completed the study according to the protocol. Mean Cmax were similar with both formulations (814.78 pg/ml for T and 781.83 pg/ml for R) and were attained at the same time (40 min. for T and 50 min. for R), and their bioavailability was also very close (AUC0-t: 3920.12 pg.h/ml for T and 3679.39 pg.h/ml for R). Bioequivalence was confirmed for the two primary parameters, Cmax and AUC0-t. No period or sequence effects were observed in any parameter. As bioequivalence was proved in the first phase of the study, it was not necessary to proceed to the second stage. The estimated intraindividual variability was 24.66% and 19.01%, respectively for T and R formulations. Both formulations were well tolerated; 15 mild adverse events were reported. Discussion: The test OTFC product is bioequivalent to the reference one and therefore interchangeable when used clinically. OTFC administration provides faster fentanyl absorption than enteral route and the rate of absorption can be modulated by the administration technique, providing a unique flexibility among all breakthrough pain treatments. The results showed a fast time to maximum concentrations (tmax), in accordance with those originally reported for the reference product, probably favoured by the strict administration technique. Proper patient education is essential to optimize the use of OTFC, as well-trained patients can take advantage of its flexibility to selfcontrolling pain relief.