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

作者：Nave Ruediger; Schmitt Holger; Popper Lars^*

来源：Drug Delivery, 2013, 20(5): 216-223.

DOI：10.3109/10717544.2012.762435

• Breakthrough cancer pain
• drug delivery system
• incomplete consumption of oral transmucosal fentanyl citrate
• pharmacokinetics
• single-dose delivery system

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 200 mu g/100 mu l) and OTFC (buccal lozenge, 200 mu g). Naltrexone was given to prevent potential adverse reactions. Frequent plasma samples were taken up to 96 h and analyzed by LC-MS/MS with a lower limit of quantitation of 25 pg/ml. Primary PK parameter was the area under the fentanyl plasma concentration-time curve (AUC(0-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 T-max. At 15 min post-dose, the mean plasma fentanyl levels reached 602 pg/ml for INFS and 29 pg/ml for OTFC. Significantly higher C-max and AUC values were obtained with INFS compared to OTFC. Although administered for 15 min, consumption of OTFC was incomplete in many incidences (similar to 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.

• 出版日期2013-7