title: Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study.
abstract: OBJECTIVE
  To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS).
  
  
  METHODS
  This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 μg; 2 × 100 μg at 4-, 2-, and 1-hour intervals, and 8 × 100 μg consecutively) were administered to the right nostril, with a ≥ 3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters-peak concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve (AUC)-were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant.
  
  
  RESULTS
  Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). C(max) and AUC(0-24) following 8 × 100 μg were approximately fivefold of those following 1 × 100 μg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs.
  
  
  CONCLUSIONS
  FPNS exhibited consistently rapid t(max). When intervals between two doses were shorter, the difference in C(max) between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.
authors.affiliation: Research & Development, Depomed Inc., Newark, California.
authors.forename: Cuiping
authors.initials: C
authors.lastname: Chen
authors.affiliation: Research & Development, Depomed Inc., Newark, California.
authors.forename: Shay
authors.initials: S
authors.lastname: Bujanover
authors.affiliation: Vice Chair, Associate Professor, Division of Pain Medicine and Regional Anesthesiology, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Anita
authors.initials: A
authors.lastname: Gupta
mesh_terms: D000281:Administration, Intranasal; D000293:Adolescent; D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D059085:Nasal Sprays; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010368:Pectins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D004338:Drug Combinations; D059085:Nasal Sprays; D010368:Pectins; D005283:Fentanyl