PMID- 20441245
OWN - NLM
STAT- MEDLINE
DCOM- 20100722
LR  - 20211020
IS  - 1173-2563 (Print)
IS  - 1173-2563 (Linking)
VI  - 30
IP  - 6
DP  - 2010
TI  - Dose proportionality of fentanyl buccal tablet in doses ranging from 600 to 1300 
      microg in healthy adult subjects: a randomized, open-label, four-period, 
      crossover, single-centre study.
PG  - 365-73
AB  - Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain 
      in patients who are already receiving, and who are tolerant to, opioid therapy 
      for underlying, persistent cancer pain. Breakthrough pain may be severe or 
      excruciating, and some patients may require high doses of rapid-onset opioids to 
      obtain adequate analgesia. The objective of this study was to assess the dose 
      proportionality of FBT over a range of 600-1300 microg in healthy subjects. This 
      was a randomized, open-label, four-period, crossover, single-centre study of FBT 
      (Fentora) conducted in healthy adult subjects who were not tolerant to opioids. 
      The study included 120 men and women aged 18-45 years with a body mass index of 
      20-30 kg/m2 who had no clinically significant findings on medical and psychiatric 
      histories, physical examination, ECG or standard clinical laboratory tests, and 
      who had a negative urine screen for drugs and alcohol. Eligible subjects were 
      randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, 
      C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 microg). 
      Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was 
      administered to block the opioid receptor-mediated effects of fentanyl. Plasma 
      fentanyl concentration was measured through 72 hours after placement of FBT. The 
      main outcome measures, maximum plasma fentanyl concentration (C(max)) and area 
      under the plasma drug concentration versus time curve from time zero to infinity 
      (AUC(infinity)), were analysed to determine dose proportionality. Other 
      pharmacokinetic parameters were also evaluated. Dose proportionality was 
      concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the 
      C(max) versus dose and AUC(infinity) versus dose curves were completely contained 
      within the range of 0.711-1.289. The safety and tolerability of FBT were assessed 
      throughout the study. The slope for C(max) versus dose was 0.8627 (90% CI 0.7730, 
      0.9525), and the slope for AUC(infinity) versus dose was 0.9330 (90% CI 0.8738, 
      0.9922). Given that the CIs for C(max) and AUC(infinity) were within the 
      predefined range of 0.711-1.289, dose proportionality was concluded over the 
      600-1300 microg range. The mean dose-normalized plasma fentanyl concentration 
      reached 80% of C(max) within 25 minutes; plasma fentanyl concentration was 
      maintained at this level for 3 hours after dose. No unexpected safety or 
      tolerability concerns were noted in the naltrexone-blocked healthy subjects. 
      Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 
      [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and 
      headache. No serious AEs were reported. The dose proportionality of FBT from 
      600-1300 microg was shown in healthy subjects. Based on the data, when FBT is 
      titrated up to 1300 microg, a predictable and linear increase in systemic 
      exposure can be expected. Currently, FBT is approved up to 800 microg. This study 
      provides pharmacokinetic data to support a potential, expanded therapeutic dose 
      range of FBT.
FAU - Darwish, Mona
AU  - Darwish M
AD  - Clinical Research, Cephalon, Inc., Frazer, Pennsylvania, USA. 
      mdarwish@cephalon.com
FAU - Kirby, Mary
AU  - Kirby M
FAU - Robertson, Philmore Jr
AU  - Robertson P Jr
FAU - Tracewell, William
AU  - Tracewell W
FAU - Xie, Fang
AU  - Xie F
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 0 (Analgesics, Opioid)
RN  - 0 (Narcotic Antagonists)
RN  - 5S6W795CQM (Naltrexone)
RN  - UF599785JZ (Fentanyl)
SB  - IM
MH  - Administration, Buccal
MH  - Adolescent
MH  - Adult
MH  - Analgesics, Opioid/administration & dosage/adverse effects/*pharmacokinetics
MH  - Area Under Curve
MH  - Cross-Over Studies
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Fentanyl/administration & dosage/adverse effects/*pharmacokinetics
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Naltrexone/pharmacology
MH  - Narcotic Antagonists
MH  - Time Factors
MH  - Young Adult
EDAT- 2010/05/06 06:00
MHDA- 2010/07/23 06:00
CRDT- 2010/05/06 06:00
PHST- 2010/05/06 06:00 [entrez]
PHST- 2010/05/06 06:00 [pubmed]
PHST- 2010/07/23 06:00 [medline]
AID - 2 [pii]
AID - 10.1007/BF03256906 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2010;30(6):365-73. doi: 10.1007/BF03256906.