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

espanolIntroduccion: El citrato de fentanilo oral transmucosa (CFOT) fue el primer medicamento disenado especificamente para tratar el dolor irruptivo. Esta formulado como una matriz de polvo comprimido con aplicador de plastico (palito), y el paciente se lo administra, lo que proporciona modulabilidad o flexibilidad de dosis. Objetivos: Probar la bioequivalencia entre el medicamento CFOT test (T) y el de referencia (R). Material y metodos: Estudio abierto, cruzado, aleatorizado, de bioequivalencia a dosis unica en voluntarios sanos, con dos periodos y dos secuencias, y con un tiempo de lavado de al menos 10 dias. Los sujetos tomaron 400 μg de fentanilo cada dia de estudio. Se les instruyo para que restregaran el comprimido contra la mucosa bucal sin chuparlo ni masticarlo, y los investigadores controlaron cada administracion para asegurar que se consumia en 15 minutos. Se establecio un diseno en dos etapas por la alta variabilidad farmacocinetica esperada, y la decision de bioequivalencia se baso en los intervalos de confianza al 94,12 % de la razon de las medias geometricas de la Cmax y el AUC0-t. Resultados: 36 sujetos completaron el estudio de acuerdo con el protocolo. Las medias de Cmax fueron similares con ambas formulaciones (814,78 pg/ml para T y 781,83 pg/ml para R) y se alcanzaron al mismo tiempo (40 min para T y 50 min para R), y su biodisponibilidad tambien fue muy semejante (AUC0-t: 3920,12 pg.h/ml para T y 3679,39 pg.h/ml para R). Se confirmo la bioequivalencia para los dos parametros principales, Cmax y AUC0-t. No se observaron efecto periodo ni secuencia para ningun parametro. Como se probo la bioequivalencia en la primera fase del estudio no fue necesario proceder a la segunda fase. La variabilidad intraindividual estimada fue 24,66 y 19,01 %, respectivamente para T y R. Los dos medicamentos fueron bien tolerados; se registraron 5 acontecimientos adversos de intensidad leve. Conclusiones: La formulacion CFOT test es bioequivalente con la de referencia, y por tanto son clinicamente intercambiables. La administracion de CFOT proporciona una absorcion mas rapida de fentanilo que la via enteral y la tasa de absorcion puede modularse con la tecnica de administracion, aportando una flexibilidad unica al resto de tratamientos del dolor irruptivo. Los resultados muestran un breve tiempo hasta concentraciones plasmaticas maximas (tmax), coincidente con el descrito originalmente para la formulacion de referencia, favorecido probablemente por la estricta tecnica de administracion. Es esencial una adecuada formacion de los pacientes para optimizar el uso de CFOT, ya que los pacientes bien entrenados pueden sacar buen provecho de su flexibilidad para auto-regularse el alivio del dolor. EnglishIntroduction: 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 self-controlling pain relief.