title: Single-dose and multi-dose delivery systems for intranasal fentanyl spray are bioequivalent as demonstrated in a replicate pharmacokinetic study.
abstract: BACKGROUND
  Intranasal fentanyl spray (INFS, Instanyl®) was developed to treat cancer patients with Breakthrough Pain (BTP). INFS is delivered via a multi-dose delivery system (MDS) that is available in various dose strengths. The aim of this study was to demonstrate the pharmacokinetic bioequivalence of INFS single dose delivery system (SDS) in relation to the currently marketed MDS device.
  
  
  METHODS
  In a randomized, single-center, single-dose, open label, comparative, four-period, two-sequence, replicate cross-over study, 48 healthy subjects (24 male and 24 female, mean age of 28.1 years, mean bodyweight 69.8 kg) received 200 μg/100 μl fentanyl administered via SDS and via MDS in one of two alternating treatment sequences. Naltrexone was given to all subjects to prevent potential fentanyl adverse drug reactions. Blood samples were frequently taken up to 72 hours post INFS administration and analyzed by liquid chromatography with tandem mass spectrometric detection. Primary pharmacokinetic parameters were area under the curve extrapolated to infinity (AUC0-∞) and peak plasma concentration (Cmax). Statistical analyses of the primary pharmacokinetic parameters were performed using a linear mixed effect model applied to the natural log-transformed data.
  
  
  RESULTS
  Healthy subjects showed very similar plasma concentration over time profiles for both delivery systems. The mean fentanyl Cmax and AUC0-∞ values for SDS and MDS were 948 pg/ml, 949 pg/ml and 4,439 pg×h/ml, 4,489 pg×h/ml. respectively. Point estimates (and 90% confidence intervals) for AUC and Cmax were 0.97 (0.93 - 1.02) and 1.00 (0.92 - 1.09) and therefore in the bioequivalence range of 0.80 - 1.25.
  
  
  CONCLUSIONS
  Results of this study show that SDS and MDS met the pre-defined regulatory criteria for bioequivalence. Safety profiles were consistent between both devices and no safety concerns were identified with INFS administered in combination with oral naltrexone.
authors.affiliation: Nycomed, a Takeda Company, Konstanz, Germany. ruediger.nave@takeda.com
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Nave
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Connolly
authors.forename: Lars
authors.initials: L
authors.lastname: Popper
authors.forename: Gezim
authors.initials: G
authors.lastname: Lahu
authors.forename: Holger
authors.initials: H
authors.lastname: Schmitt
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016503:Drug Delivery Systems; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013810:Therapeutic Equivalency
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl