Faster absorption and higher systemic bioavailability of intranasal fentanyl spray compared to oral transmucosal fentanyl citrate in healthy subjects

摘要

Context: Intranasal fentanyl spray (INFS) was developed for the treatment of breakthrough pain in cancer patients using an alternative route of administration. Objective: The aim of this clinical study was to investigate the pharmacokinetic (PK) profile and bioavailability of INFS in healthy subjects compared to oral transmucosal fentanyl citrate (OTFC). Materials and methods: In a randomized, single-center, open-label, two-way crossover PK study, 24 subjects (12 male, 12 female, mean age 25.2 years) received INFS (single-dose delivery system 200μg/100μl) and OTFC (buccal lozenge, 200g). Naltrexone was given to prevent potential adverse reactions. Frequent plasma samples were taken up to 96h and analyzed by LC-MS/MS with a lower limit of quantitation of 25pg/ml. Primary PK parameter was the area under the fentanyl plasma concentration-time curve (AUC0-inf). Results: Compared to OTFC, a much faster absorption rate was observed for INFS which was supported by the much earlier appearance of detectable fentanyl plasma levels and a shorter Tmax. At 15min post-dose, the mean plasma fentanyl levels reached 602pg/ml for INFS and 29pg/ml for OTFC. Significantly higher Cmax and AUC values were obtained with INFS compared to OTFC. Although administered for 15min, consumption of OTFC was incomplete in many incidences (～70%) upon visual inspection. No safety concerns were identified for fentanyl administration in combination with oral naltrexone. Discussion and conclusion: One dose of INFS gives significantly higher plasma fentanyl levels and significantly higher bioavailability than OTFC based on dose-normalized AUC.