Advertisement

Clinical Drug Investigation

, Volume 28, Issue 1, pp 1–7 | Cite as

Bioequivalence Following Buccal and Sublingual Placement of Fentanyl Buccal Tablet 400 μg in Healthy Subjects

  • Mona DarwishEmail author
  • Mary Kirby
  • John G. Jiang
  • William Tracewell
  • Philmore RobertsonJr
Original Research Article

Abstract

Background and objective:

The fentanyl buccal tablet (FBT) is formulated to enhance the rate and extent of fentanyl absorption across the buccal mucosa. FBT is indicated for the management of breakthrough pain (a transient flare of pain on a background of chronic pain otherwise controlled by treatment with opioids) in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. This study assessed the bioequivalence of a single 400-μg dose of FBT following buccal (i.e. above a molar tooth between the upper gum and cheek) and sublingual (i.e. placed under the tongue) placement in order to provide an alternative option to patients.

Methods:

Healthy subjects were randomized to receive one FBT 400 μg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC), was established if the 90% confidence interval (CI) for the ratio of the means of sublingual/buccal values fell within the range of 0.80 to 1.25.

Results:

Ninety subjects were enrolled (67 men, 23 women; median age 24 years), and 78 completed the study. The criteria for bioequivalence were met for both Cmax and AUC for the two sites of tablet placement: sublingual/buccal ratio for Cmax = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to tmax′ (AUCtmax′), where tmax′ is the median time to Cmax of a single 400-μg dose of FBT administered buccally (mean [SD]: 0.35 [0.16] ng · h/mL buccal; 0.35 [0.16] ng · h/mL sublingual) and for time to Cmax (median [range]: 0.75 [0.33–3.13] hours buccal; 0.78 [0.17–3.00] hours sublingual). FBT was generally well tolerated following placement at both sites in healthy volunteers administered naltrexone.

Conclusion:

The results of this study support sublingual FBT placement as a viable alternative to buccal placement in patients who may require an alternate administration site.

Keywords

Fentanyl Naltrexone Breakthrough Pain Fentanyl Buccal Tablet Median Tmax 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This study was sponsored by Cephalon, Inc. (Frazer, PA, USA). The authors are employed by the sponsoring company. The authors would like to thank the investigator (Alan S. Marion, MD, CCTI, of MDS Pharma Services, Lincoln, NE, USA) and the subjects who participated in this study. Writing assistance was provided by Embryon.

References

  1. 1.
    Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbrid LE, Gilman AG, editors. Goodman & Gilman’s The pharmacologic basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001: 569–619Google Scholar
  2. 2.
    Durfee S, Messina J, Khankari R. Fentanyl effervescent buccal tablets: enhanced buccal absorption. Am J Drug Deliv 2006; 4(1): 1–5CrossRefGoogle Scholar
  3. 3.
    Stanley TH. Fentanyl. J Pain Symptom Manage 2005 May; 29(5 Suppl.): S67–71PubMedCrossRefGoogle Scholar
  4. 4.
    Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 1999 May; 81(1–2): 129–34PubMedCrossRefGoogle Scholar
  5. 5.
    Slatkin NE, Xie F, Messina J, et al. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain: a double-blind, randomized, placebo-controlled study. J Support Oncol 2007 Jul–Aug; 5(7): 327–34PubMedGoogle Scholar
  6. 6.
    Portenoy RK, Taylor D, Messina J, et al. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 2006 Nov–Dec; 22(9): 805–11PubMedCrossRefGoogle Scholar
  7. 7.
    Shojaei AH. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm Pharm Sci 1998; 1: 15–30PubMedGoogle Scholar
  8. 8.
    Darwish M, Tempero K, Kirby M, et al. Pharmacokinetics and dose proportionality of fentanyl effervescent buccal tablets in healthy volunteers. Clin Pharmacokinet 2005; 44(12): 1279–86PubMedCrossRefGoogle Scholar
  9. 9.
    Darwish M, Kirby M, Robertson Jr P, et al. Pharmacokinetic properties of fentanyl effervescent buccal tablets: a phase I, open-label, crossover study of single-dose 100, 200, 400 and 800 μg in healthy adult volunteers. Clin Ther 2006 May; 28(5): 707–14PubMedCrossRefGoogle Scholar
  10. 10.
    Darwish M, Kirby M, Robertson Jr P, et al. Single-dose and steady-state pharmacokinetics of fentanyl buccal tablet in healthy volunteers. J Clin Pharmacol 2007 Jan; 47(1): 56–63PubMedCrossRefGoogle Scholar
  11. 11.
    Gibaldi M, Perrier D. Noncompartmental analysis based on statistical moment theory. In: Gibaldi M, Perrier D, editors. Pharmacokinetics. 2nd ed. New York: Marcel Dekker Inc., 1982: 409–17Google Scholar
  12. 12.
    Darwish M, Kirby M, Robertson P, et al. Comparison of equivalent doses of fentanyl buccal tablets and arteriovenous differences in fentanyl pharmacokinetics. Clin Pharmacokinet 2006; 45(8): 843–50PubMedCrossRefGoogle Scholar
  13. 13.
    Darwish M, Kirby M, Jiang JG. Effect of buccal dwell time on the pharmacokinetic profile of fentanyl buccal tablet. Expert Opin Pharmacother 2007 Sep; 8(13): 2011–6PubMedCrossRefGoogle Scholar
  14. 14.
    Darwish M, Tempero K, Kirby M, et al. Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1080 μg versus oral transmucosal fentanyl citrate 1600 μg and dose proportionality of FEBT 270 to 1300 μg: a single-dose, randomized, open-label, three-period study in healthy adult volunteers. Clin Ther 2006 May; 28(5): 715–24PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Mona Darwish
    • 1
    Email author
  • Mary Kirby
    • 1
  • John G. Jiang
    • 2
  • William Tracewell
    • 3
  • Philmore RobertsonJr
    • 3
  1. 1.Clinical Pharmacology, Cephalon, Inc.FrazerUSA
  2. 2.Biostatistics, Cephalon, Inc.FrazerUSA
  3. 3.Drug Disposition, Cephalon, Inc.West ChesterUSA

Personalised recommendations