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

Abstract

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 mg/100 ml) and OTFC (buccal lozenge, 200 mg). 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 ($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. KeywordsBreakthrough cancer pain, drug delivery system, incomplete consumption of oral transmucosal fentanyl citrate, pharmacokinetics, single-dose delivery system History

A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats

“…The doses of fentanyl used in the current study generated clinically relevant serum fentanyl concentrations in the range of 5-30 ng/ml. In humans, therapeutic serum concentrations of fentanyl show a C max ranging from 0.2 to 0.9 ng/ml after sublingual, intranasal, transmucosal fentanyl, or intravenous administration of fentanyl (Nave et al, 2013;Parikh et al, 2013), whereas unintentional overdose of transdermal patches show fentanyl blood concentrations ranging from 5 to 28 ng/ml (Jumbelic, 2010) and respiratory depression at plasma concentrations of 2.5-6.3 ng/ml in humans (Mildh et al, 2001).…”

Intranasal delivery of FSD‐C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

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“…[24][25][26] In this study, we explored whether intranasal administration of FSD-C10 could modulate systemic immune responses in EAE mice. As shown in Fig.…”

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“…[39][40][41] After single-dose administration ranging from 75 to 200 μg, C max have been 0.7-1.7 ng/mL across studies. 39,[41][42][43][44] In cancer patients, elimination halflife (mean ± SD) was 193 ± 106, 255 ± 190, and 209 ± 79 minutes for a single dose of 50, 100, and 200 μg, respectively. 41 In comparison with another study in a different patient population, elimination half-lives of 89-279 minutes at doses of 75, 100, 150, and 200 μg have been reported.…”