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Intranasal fentanyl showed kinetic and dynamic properties that are desirable for the management of acute, episodic (breakthrough) pain.

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

No abstract

Pharmacokinetic (PK) and pharmacodynamic (PD) data were available from a study of a nasal delivery system for the opioid analgesic fentanyl, together with data on the kinetics of fentanyl in arterial blood in man, and in the lung and brain of sheep. Our aim was to reconcile these data using a physiologically-based population recirculatory PK-PD model, with emphasis on achieving a meta-model that could simultaneously account for the arterial and venous (arm) concentrations of fentanyl, could relate PD effects (pain scores) to the CNS concentrations of fentanyl, and could account for the effect of body size and age on fentanyl kinetics. Data on the concentration gradients of fentanyl across brain, lung and muscle were used to develop sub-models of fentanyl kinetics in these organs. The sub-models were incorporated into a "whole body" recirculatory model by adding additional sub-models for a venous mixing compartment, the liver and gut, the kidney and the "rest of the body" with blood flows and organ volumes based on values for a Standard Man. Inter-individual variability was achieved by allometric scaling of organ size and blood flows, evidence-based assumptions about the effect of weight and age on cardiac output, and inter-individual variability in the free fraction in plasma and hepatic extraction of fentanyl. Post-operative pain scores were found to be temporally related to the predicted brain concentrations of fentanyl. We conclude that a physiologically-based meta-modelling approach was able to describe clinical PK-PD studies of fentanyl whilst providing a mechanistic interpretation of key aspects of its disposition.