Evaluation of the single- and multiple-dose pharmacokinetics of fentanyl buccal soluble film in normal healthy volunteers.

Abstract

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations (mean C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) increased approximately 3-fold with the 3-dose regimen compared with the single-dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

Full text

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Evaluation of the Single- and Multiple-Dose
Pharmacokinetics of Fentanyl Buccal Soluble Film
in Normal Healthy Volunteers
Niraj Vasisht, PhD
Larry N. Gever, PharmD
Ignacio Tagarro, PhD
Andrew L. Finn, PharmD
jULY 2010
VoLUme 50
NUmber 7
Reprinted from
Available online to ACCP members at www.ACCP1.org
Available online to institutional subscribers at www.jclinpharm.org

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J Clin Pharmacol xxxx;xx:x-x J Clin Pharmacol 2010;50:785-791
785785
C
on a regular schedule. However, patients with can-
cer may also experience acute transient exacerba-
tions of pain beyond their otherwise stable, persistent
pain.1 This “breakthrough pain” can be sudden and
very intense, and optimal management usually
requires potent, fast-acting opioid analgesics.2 The
oral route of administration is the most commonly
used; however, the effectiveness of oral opioids may
be limited by relatively slow gastrointestinal absorp-
tion and first-pass metabolic effects. Additionally,
oral delivery of analgesics can be problematic for
patients who have difficulty swallowing or have
gastrointestinal conditions.3
hronic pain in patients with cancer is usually
managed with long-term analgesic therapy taken
The limitations of orally administered pain medi-
cations have led to the development of transmucosal
delivery systems using the opioid fentanyl. Fentanyl,
a µ-receptor agonist whose analgesic effect arises
from its ability to inhibit the signals from the pain
transmission system and activate pain control cir-
cuits,4 is considered ideal for transmucosal delivery
for a number of reasons. Fentanyl is up to 100 times
as potent as morphine,5 is highly lipophilic in
nature, and is metabolized in the liver by cyto-
chrome P450 3A4 to the inactive metabolite, norfen-
tanyl.6 Finally, fentanyl has a rapid onset of action
and relatively short duration of effect that are con-
sistent with the temporal characteristics of break-
through cancer pain.7
The transmucosal delivery of fentanyl has been
studied in animal models. Fentanyl was adminis-
tered to 6 dogs via a specially constructed cell
attached to the dogs’ buccal mucosa for approxi-
mately 1 hour.8 The results of that study showed that
absorption, bioavailability, and permeability of fen-
tanyl through the oral mucosa were dependent on
pH of the delivery solution. In another study,9 pig
esophageal mucosa was used to examine fentanyl
Fentanyl buccal soluble film (FBSF) is a rapidly absorbed
transmucosal formulation of fentanyl for the management
of breakthrough pain in opioid-tolerant patients with can-
cer. This open-label, 3-period, sequential dose study
evaluated the dose-to-dose reproducibility of the pharma-
cokinetics of fentanyl following the administration of 600-
or 1800-µg doses of FBSF in 12 naltrexone-blocked,
healthy adult volunteers. Subjects received 3 study treat-
ments: single doses of 600 µg of FBSF on day 1 and day 4
and three 600-µg doses administered at 1-hour intervals
on day 7. Plasma fentanyl concentrations were measured
over a 48-hour period after each single dose of FBSF and
72 hours after the 3-dose regimen. Peak plasma concentra-
tions (mean Cmax = 1.08 and 1.01 ng/mL) and overall
exposure (mean AUC0-12 = 6.3 and 6.2 h·ng/mL; mean
AUCinf = 9.14 and 9.60 h·ng/mL) were nearly identical after
the 2 single doses (P ≥ .1, all comparisons). Cmax and over-
all fentanyl exposure (AUCinf) increased approximately
3-fold with the 3-dose regimen compared with the single-
dose periods. Fentanyl plasma concentrations following
single doses of FBSF were reproducible, and 3 doses
administered 1 hour apart produced a tripling in exposure
and maximal concentration compared with a single dose.
Keywords:? Buccal; drug absorption; fentanyl; opioids;
pharmacokinetics; transmucosal
Journal?of?Clinical?Pharmacology,?2010;50:785-791
©?2010?The?Author(s)
From BioDelivery Sciences International, Inc., Raleigh, North Carolina
(Dr Vasisht, Dr Finn); Meda Pharmaceuticals, Inc., Somerset, New Jersey
(Dr Gever); and Meda Pharma, Madrid, Spain (Dr Tagarro). Submitted
for publication July 24, 2009; revised version accepted December 27,
2009. Address for correspondence: Andrew L. Finn, PharmD, BioDelivery
Sciences International, 801 Corporate Center Drive, Suite 210, Raleigh,
NC 27607; e-mail: afinn@bdsinternational.com.
DOI:10.1177/0091270010361354
Evaluation of the Single- and Multiple-Dose
Pharmacokinetics of Fentanyl Buccal Soluble
Film in Normal Healthy Volunteers
Niraj Vasisht, PhD, Larry N. Gever, PharmD, Ignacio Tagarro, PhD,
and Andrew L. Finn, PharmD

Page 4

786 • J Clin Pharmacol 2010;50:785-791
VASISHT ET AL
transport after administration via a polyvinylpyrro-
lidone bioadhesive film. The delivery of fentanyl
across the esophageal membrane at all pHs suggests
that fentanyl transport is aided by the film itself.
Oral transmucosal delivery of fentanyl has also been
studied in humans.10 In a 4-period crossover study,
healthy volunteers were administered oral transmu-
cosal fentanyl citrate (OTFC) lozenge, a transmucosal
fentanyl buccal tablet (FBT), intravenous fentanyl, and
oral FBT. Administration of transmucosal FBT resulted
in greater absorption than OTFC and oral FBT.
Although fentanyl can be administered by oral
transmucosal delivery, dose-to-dose variations in the
mucosal surface area exposed to fentanyl and its
contact time with that surface area can lead to sub-
stantial variability in peak plasma concentrations
and overall bioavailability.11,12 This seems particu-
larly relevant in the case of OTFC because the frac-
tion of drug transmucosally absorbed and swallowed
strongly depends upon the application technique
used by individual patients.
Fentanyl buccal soluble film (FBSF) uses the
BioErodible MucoAdhesive (BEMA, BioDelivery
Sciences, Raleigh, NC) drug delivery system for
transmucosal delivery of fentanyl to treat break-
through cancer pain. This delivery system consists of
a small bilayered, water-erodible polymer film that
adheres to the buccal mucosa and completely dis-
solves in 15 to 30 minutes. The fentanyl is contained
in the mucoadhesive layer that is isolated from the
saliva by the non–drug-containing layer, facilitating
unidirectional drug flow across the buccal mucosa.
The effect of pH on the exposure of FBSF has
been evaluated.13 The pharmacokinetic profiles of
FBSF at 3 different pHs (pH 6, pH 7.25, and pH 8.5)
were compared in healthy volunteers. Each formula-
tion produced overall exposures greater than OTFC;
however, the pH 7.25 FBSF formulation exhibited
significantly higher maximum drug concentration in
plasma (Cmax) and area under the concentration-time
curve (AUC) compared with OTFC.
This phase 1 study was designed to evaluate the
dose-to-dose reproducibility of fentanyl absorption
and the sequential dose pharmacokinetics following
FBSF administration in healthy volunteers.
MEtHoDS
Subjects
Eligible volunteers were males or females aged 18 to
35 years, with a body weight of 50 to 100 kg and
within 15% of ideal body weight based on
Metropolitan Life tables for height and weight.14
Volunteers were required to be free of any significant
clinical abnormalities on the basis of medical his-
tory, physical examination, electrocardiogram, and
screening laboratory tests. Subjects were required to
be nonsmokers for at least 30 days prior to screen-
ing. Subjects were excluded from the study if they
had any significant medical condition, either cur-
rently or by history (including glaucoma and seizure
disorders); had participated in any investigational
drug study within the past 30 days; had a recent his-
tory or current evidence of alcohol or other sub-
stance abuse; had taken any concomitant medication
other than oral contraceptives or acetaminophen
within 72 hours prior to the first dose of study
medication; or had a significant history of intoler-
ance to narcotics or naltrexone and, in the opinion
of the investigator, would be unlikely to tolerate fen-
tanyl or naltrexone. Women of childbearing poten-
tial who were not using a medically accepted method
of contraception or had a positive urine β-human
chorionic gonadotropin test were also excluded.
The study was conducted at a single phase 1
clinical research unit (CEDRA Clinical Research,
LLC, Austin, Texas) in accordance with the ethical
principles set forth in the Declaration of Helsinki,
the Code of Federal Regulations, title 21, part 50,
and in compliance with local regulations. The proto-
col was reviewed and approved by an institutional
review board (IntegReview Ethical Board, Austin,
Texas) prior to study conduct. Prior to any study
procedure, subjects provided written informed con-
sent after having received information on the proce-
dures, possible hazards, and risks of the study.
Study Design
This was an open-label, multiple-dose, 3-period
investigation conducted over 10 days. Eligible sub-
jects reported to the study center by 6 p.m. on day 0
and remained in the unit through day 10. Subjects
received a single 600-µg dose of FBSF (Onsolis,
Meda Pharmaceuticals, Somerset, NJ) on day 1
(period 1), a single 600-µg dose on day 4 (period 2),
and 3 consecutive 600-µg doses at 1-hour intervals
on day 7 (period 3). A schematic of subject progres-
sion through the study is presented in Figure 1.
Subjects were given oral naltrexone 50 mg at approx-
imately 6 p.m. the evening prior to each dose and at
approximately 6 a.m. and 6 p.m. on the day of study
drug administration. Naltrexone was administered

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FENTANYL BUCCAL SOLUBLE FILM
PhARMACOkINeTICS
787
to block the opioid-mediated effects of fentanyl.
Each FBSF dose was placed on the buccal mucosa
inside of the right cheek next to the lower teeth and
held in place for 5 seconds until it adhered to the
mucosa.
Blood samples were collected just prior to the
initial dose on each study day and at 15, 30, and 45
minutes and 1, 2, 3, 4, 8, 12, 16, 20, 24, and 48 hours
after the initial study dose. Additional samples from
period 3 were obtained 15 minutes after each addi-
tional dose as well as at 5, 6, 10, and 72 hours after
the initial dose.
Safety measures included physical examinations,
electrocardiograms, and clinical laboratory tests at
screening and day 10. Vital signs and pulse oximetry
were monitored during the first 4 hours after each
study drug dose. Adverse events were collected
throughout the study.
Bioanalytical Methods
Plasma samples collected in K3EDTA were analyzed
at the end of the study for fentanyl using a validated
liquid chromatography and tandem mass spectro-
photometry procedure with a lower limit of quanti-
fication of 0.0250 ng/mL and an upper limit of 5.00
ng/mL based on the analysis of 0.500 µL of EDTA
human plasma. The internal standard was fentanyl-
D5 at a concentration of 0.25 µg/mL. Quantification
was performed using a weighted (1/X2) linear least-
squares regression analysis generated from calibra-
tion standards. The assay procedure was found to be
linear over the range of 0.0254 to 5.00 ng/mL with a
mean correlation coefficient of 0.9992. The coeffi-
cient of variation of calibration standard curves
ranged from 1.3% to 5.4%. The absolute deviation of
the mean from the theoretical concentration ranged
from 0.00% to 2.3%. Accuracy was evaluated by
treating the peak areas of the calibration standards as
unknowns and entering them into the derived equa-
tion for the least squares regression line to obtain
amount found values. The absolute deviation of the
amount found from the theoretical concentration
ranged from 0.8% to 7.2%. To examine specificity,
blank samples of EDTA plasma were analyzed, with
no interferences observed at the retention times of
fentanyl or the internal standard.
Data Analysis and Statistics
Pharmacokinetic analyses used noncompartmental
methods in WinNonlin version 4.0 (Pharsight,
Mountain View, Calif), and data from all subjects
were included. Pharmacokinetic calculations were
based on actual sampling times. Concentrations that
were below the limit of quantification (BLQ)
(<0.0250 ng/mL) were treated as zero (0.00 ng/mL)
in the data summarization and descriptive statis-
tics. Embedded or terminal BLQ concentrations
were treated as missing. In the pharmacokinetic
analysis, BLQ concentrations were treated as zero
when preceding the Cmax and treated as missing val-
ues following the Cmax for estimation of mean
concentration-time curves. Full precision concen-
tration data were used for all pharmacokinetic and
statistical analyses.
Maximum drug concentration in plasma (Cmax),
first measurable drug concentration (Cfirst), time to
first measurable concentration (Tfirst), and time to
Cmax (Tmax) were determined from individual subject
concentration-time profiles. AUC was calculated
using the linear trapezoidal rule. Area under the
concentration-time curve from T0 extrapolated to
infinity (AUCinf) was calculated as AUClast + Clast / λz,
where AUClast is the AUC from T0 to the time of the
last quantifiable concentration, Clast is the last quan-
tifiable concentration, and λz is the observed elimi-
nation rate constant. Calculation of λz was performed
using unweighted linear regression analysis on at
least 3 log-transformed concentrations visually
assessed to be on the linear portion of the terminal
slope. Area under the concentration-time curve from
time 0 to 12 hours postdose (AUC0-12) was extrapo-
lated using the elimination rate constant if measurable
Figure 1. Progression of study subjects through the 3 periods of the study. FBSF, fentanyl buccal soluble film.