Bioequivalence following buccal and sublingual placement of fentanyl buccal tablet 400 microg in healthy subjects.
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-microg 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 microg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (C(max)) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC(infinity)), 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 C(max) and AUC(infinity) for the two sites of tablet placement: sublingual/buccal ratio for C(max) = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC(infinity) = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to t(max') (AUC(tmax')), where t(max') is the median time to C(max) of a single 400-microg 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 C(max) (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.


CONCLUSIONS
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.
Darwish
Mona
M
Clinical Pharmacology, Cephalon Inc, Frazer, PA 19355, USA. mdarwish@cephalon.com
Kirby
Mary
M
Jiang
John G
JG
Tracewell
William
W
Robertson
Philmore
P
D000278:Administration, Buccal; D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005283:Fentanyl / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010352:Patient Dropouts / Q000706:statistics & numerical data; D017450:Receptors, Opioid, mu / Q000819:agonists; D013607:Tablets; D013810:Therapeutic Equivalency; D014839:Vomiting / Q000139:chemically induced
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D013607:Tablets; D005283:Fentanyl