Comparison of equivalent doses of fentanyl buccal tablets and arteriovenous differences in fentanyl pharmacokinetics.
BACKGROUND
The fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa.


OBJECTIVE
To evaluate the bioequivalence of microg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers.


METHODS
Twenty-seven healthy adults, aged 19-45 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100 microg tablets simultaneously or one FBT 400 microg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400 microg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout.


RESULTS
Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100 microg tablets simultaneously compared with one FBT 400 microg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study.


CONCLUSIONS
Despite small differences in C(max) and AUC(infinity) (on average 12% and 13%, respectively), FBT administered as four 100 microg tablets simultaneously compared with one 400 microg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum concentrations observed with four 100 microg tablets. A substantially higher C(max) was reached earlier in the arterial than in the venous circulation.
Darwish
Mona
M
Clinical Pharmacology, Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
Kirby
Mary
M
Robertson
Philmore
P
Hellriegel
Edward
E
Jiang
John G
JG
D000278:Administration, Buccal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism*; D013607:Tablets; D013810:Therapeutic Equivalency
D000701:Analgesics, Opioid; D013607:Tablets; D005283:Fentanyl