Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study

Cuiping Chen, PhD; Shay Bujanover, MD; Anita Gupta, DO, PharmD

doi:10.5055/jom.2015.0263

Authors

Cuiping Chen, PhD
Shay Bujanover, MD
Anita Gupta, DO, PharmD

DOI:

https://doi.org/10.5055/jom.2015.0263

Keywords:

fentanyl pectin nasal spray, multiple-dose, dosing interval, pharmacokinetics, rate of absorption, breakthrough cancer pain

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 (Cmax), time to Cmax (tmax), 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). Cmax and AUC0-24 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 tmax. When intervals between two doses were shorter, the difference in Cmax 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.

Author Biographies

Cuiping Chen, PhD

Research & Development, Depomed Inc., Newark, California

Shay Bujanover, MD

Research & Development, Depomed Inc., Newark, California

Anita Gupta, DO, PharmD

Vice Chair, Associate Professor, Division of Pain Medicine and Regional Anesthesiology, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania

References

Davies AN: Breakthrough cancer pain. Curr Pain Headache Rep. 2014; 18(6): 420-429.

American Pain Foundation: Breakthrough cancer pain: Mending the break in the continuum of care. J Pain Palliat Care Pharmacother. 2011; 25(3): 252-264.

Chen C, Gupta A: Clinical and pharmacokinetic considerations of novel formulations of fentanyl for breakthrough cancer pain. Future Med. 2014; 4(5): 339-350.

Actiq Prescribing Information. Available at http://www.actiq.com/pdf/actiq_package_insert_4_5_07.pdf. Accessed August 11, 2014.

Fentora Prescribing Information. Available at http://www.fentora.com/pdfs/pdf100_prescribing_info.pdf. Accessed August 11, 2014.

Onsolis Prescribing Information. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022266s000lbl.pdf. Accessed August 11, 2014.

Abstral Prescribing Information. Available at https://www.tirfremsaccess.com/TirfUI/rems/pdf/abstral-prescribing-information.pdf. Accessed August 11, 2014.

Subsys Prescribing Information. Available at http://subsysspray.com/assets/subsys/client_files/files/PrescribingInfo.pdf. Accessed August 11, 2014.

Lazanda Prescribing Information. Available at http://www.lazanda.com/sites/all/themes/lazanda/pdfs/Lazanda_Prescribing_Information.pdf. Accessed August 11, 2014.

Janssen PA: A review of the chemical features associated with strong morphine-like activity. Br J Anaesth. 1962; 34(4): 260-268.

Pasternak GW: Pharmacological mechanisms of opioid analgesia. Clin Neuropharmacol. 1993; 16(1): 1-18.

Gustein HB, Akil H: Opioid analgesics. In Brunton LL, Laso JS, Parker KL (eds.): Goodman & Gilman's the Pharmacological Basis of Therapeutics. McGraw-Hill Companies, Inc., 2006: 547-590.

De Luca A, Coupar IM: Insights into opioid action in the intestinal tract. Pharmacol Ther. 1996; 69(2): 103-115.

De Scheper HU, Cremonini F, Park MI, et al.: Opioids and the gut: Pharmacology and current clinical experience. Neurogastroenterol Motil. 2004; 16(4): 383-394.

Benyamin R, Trescot AM, Datta S, et al.: Opioid complications and side effects. Pain Physician. 2008; 11(2 suppl): S105-S120.

McLain DA, Hug CC: Intravenous fentanyl kinetics. Clin Pharmacol Ther. 1980; 28(1): 106-114.

Tegeder I, Lötsch J, Geisslinger G: Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet. 1999; 37(1): 17-40.

Smith HS: Considerations in selecting rapid-onset opioids for the management of breakthrough pain. J Pain Res. 2013; 6(3): 189-200.

Zucco F, Bonezzi C, Fornasari D: Breakthrough Cancer Pain (BTcP): A synthesis of taxonomy, pathogenesis, therapy, and good clinical practice in adult patients in Italy. Adv Ther. 2014; 31(7): 657-682.

Taylor DR, Gabrail N: Fentanyl pectin nasal spray for breakthrough cancer pain. Future Oncol. 2012; 8(2): 121-130.

Fisher A, Watling M, Smith A, et al.: Pharmacokinetic comparisons of three nasal fentanyl formulations: Pectin, chitosan and chitosan-poloxamer 188. Int J Clin Pharmacol Ther. 2010; 48(2): 138-145.

Foster D, Upton R, Christrup L, et al.: Pharmacokinetics and pharmacodynamics of intranasal versus intravenous fentanyl in patients with pain after oral surgery. Ann Pharmacother. 2008; 42(10): 1380-1387.

Fisher A, Watling M, Smith A, et al.: Pharmacokinetics and relative bioavailability of fentanyl pectin nasal spray 100–800 μg in healthy volunteers. Int J Clin Pharmacol Ther. 2010; 48(12): 860-867.

Portenoy RK, Burton AW, Gabrail N, et al.: A multicenter, placebo-controlled, double-blind, multiple crossover study of fentanyl pectin nasal spray (FPNS) in the treatment of breakthrough cancer pain. Pain. 2010; 151(3): 617-624.

Taylor D, Galan V, Weinstein SM, et al.: Fentanyl pectin nasal spray in breakthrough cancer pain. J Support Oncol. 2010; 8(4): 184-190.

Perelman M, Knight A: A pharmacokinetic assessment of an alternative titration strategy for fentanyl pectin nasal spray. Int J Clin Pharmacol Ther. 2013; 51(12): 942-947.

Portenoy RK, Raffaeli W, Torres LM, et al.: Long-term safety, tolerability, and consistency of effect of fentanyl pectin nasal spray for breakthrough cancer pain in opioid-tolerant patients. J Opioid Manag. 2010; 6(5): 319-328.

Fallon M, Reale C, Davies A, et al.: Efficacy and safety of fentanyl pectin nasal spray compared with immediate-release morphine sulfate tablets in the treatment of breakthrough cancer pain: A multicenter, randomized, controlled, double-blind, double-dummy multiple-crossover study. J Support Oncol. 2011; 9(6): 224-231.

Christrup LL, Foster D, Popper LD, et al.: Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: A randomized, double-blind, double-dummy, two-way, crossover study. Clin Ther. 2008; 30(3): 469-481.

Dale O, Thoner J, Nilsen T, et al.: Serum and cerebrospinal fluid morphine pharmacokinetics after single doses of intravenous and intramuscular morphine after hip replacement surgery. Eur J Clin Pharmacol. 2007; 63(9): 837-842.

Radbruch L, Torres LM, Ellershaw JE, et al.: Long term tolerability, efficacy and acceptability of fentanyl pectin nasal spray for breakthrough cancer pain. Support Care Cancer. 2012; 20(3): 563-573.