Pain Medicine 2010; 11: 1017–1023
`Wiley Periodicals, Inc.
`
`Single-Dose Pharmacokinetics of Fentanyl
`Buccal Soluble Film
`
`Niraj Vasisht, PhD,* Larry N. Gever, PharmD,†
`Ignacio Tagarro, PhD,‡ and Andrew L. Finn,
`PharmD*
`
`*BioDelivery Sciences International, Inc., Raleigh,
`North Carolina;
`
`†Meda Pharmaceuticals, Inc., Somerset, New Jersey,
`USA;
`
`Conclusions. Fentanyl buccal soluble film effec-
`tively delivers a high percentage of the administered
`fentanyl dose and nearly identical plasma profiles
`are obtained when equivalent doses are delivered
`by single or multiple dosage units.
`
`Key Words. Breakthrough Pain; Buccal Absorption;
`Buccal Soluble Film; Drug Absorption; Fentanyl;
`Pharmacokinetics
`
`‡Meda Pharma S.A.U., Madrid, Spain
`
`Introduction
`
`Reprint requests to: Andrew L. Finn, PharmD,
`BioDelivery Sciences International, Inc., 801
`Corporate Center Drive, Suite 210, Raleigh, NC
`27607, USA. Tel: 919-582-0299; Fax: 919-582-9051;
`E-mail: afinn@bdsinternational.com.
`Re-use of this article is permitted in accordance with
`the Terms and Conditions set out at http://www3.
`interscience.wiley.com/authorresources/onlineopen.
`html
`
`Abstract
`
`Objective. The objectives of the study were to deter-
`mine the absolute bioavailability of fentanyl from
`fentanyl buccal soluble film, estimate the percent-
`age of a fentanyl dose absorbed through the buccal
`mucosa, and compare the bioavailability of equiva-
`lent doses administered either as single or multiple
`dose units.
`
`Design. Open-label, randomized, four-period, Latin-
`square crossover pharmacokinetic study.
`
`Setting. Inpatient phase 1 unit.
`
`Patients. Twelve healthy volunteers.
`
`Interventions. Injectable fentanyl citrate (200 mg)
`administered by intravenous infusion,
`injectable
`fentanyl citrate (800 mg/16 mL) administered orally,
`and fentanyl buccal soluble film (800 mg) adminis-
`tered as a single film and as four separate 200 mg
`films simultaneously.
`
`Outcome Measures. Plasma concentrations after
`fentanyl dosing; pharmacokinetic parameters.
`
`Results. The two buccal film treatments were
`bioequivalent and both had an absolute bioavailabil-
`ity of 71%. The percentage of an administered dose
`absorbed through the buccal mucosa was calcu-
`lated to be 51%.
`
`in
`Breakthrough pain has been estimated to occur
`approximately 65% of patients with cancer whose pain is
`significant enough to require opioid analgesics [1]. Man-
`agement of breakthrough pain in patients with cancer is a
`challenge because onset of breakthrough pain is fre-
`quently unpredictable, and episodes vary in both intensity
`and duration [2]. Breakthrough pain episodes can be
`associated with the end of a dosing interval
`in patients
`with inadequate baseline analgesia, may be associated
`with a precipitating event, or may be spontaneous. Epi-
`sodes can reach maximal intensity within 3–5 minutes and
`occur with a mean frequency of four to seven times daily
`[3,4]. Immediate-release oral opioids are frequently used
`for the treatment of breakthrough pain, but analgesia may
`be delayed within the required therapeutic time frame [2].
`
`The ideal drug for breakthrough pain would produce anal-
`gesia in a time frame temporal
`to the pain episode.
`However, this is only achievable with patient-controlled
`intravenous analgesia [2]. Alternative routes of administra-
`tion differ significantly from this ideal
`in speed of onset,
`consistency of effect, and patient convenience. The oral
`route is commonly selected for convenience, but analge-
`sia may be delayed due to the time required to reach
`intestinal absorption sites as well as by delays in gas-
`trointestinal motility associated with a background opioid,
`or reduced by first-pass metabolism. Additionally, oral
`delivery of analgesics can be problematic for patients who
`have difficulty swallowing, are nauseated, or have other
`gastrointestinal conditions.
`
`Alternative dosage forms that provide acute relief of
`breakthrough pain may be beneficial
`for appropriate
`patients.
`
`Buccal administration can deliver lipophilic opioids rapidly
`to the systemic circulation through the buccal mucosa,
`limiting gastrointestinal motility and first-pass metabolism
`[5]. Two forms of fentanyl citrate have been approved in
`the United States for the treatment of breakthrough pain in
`patients with cancer including an oral transmucosal fen-
`Inc.,
`lozenge (Actiq®, Cephalon,
`tanyl citrate (OTFC)
`
`1017
`
`Page 1 of 7
`
` Insys Exhibit 2026
`CFAD v. Insys
`IPR2015-01800
`
`

`
`Vasisht et al.
`
`Frazer, PA) and a fentanyl effervescent buccal tablet (FBT)
`(US: Fentora®, Europe: Effentora®, Cephalon, Inc.; Frazer)
`[6]. A relatively wide range of variability in plasma concen-
`trations has been reported with the OTFC lozenge, likely
`because the fraction of the dose that is swallowed may
`vary from dose to dose depending upon how exactly the
`device is applied at each occasion. With FBT [7], the
`dosing range is limited by nonlinear pharmacokinetics
`above 800 mg [8]. Further, there are differences in phar-
`macokinetics between multiple units of a lower strength
`(4 ¥ 100 mg) and a single higher strength (400 mg) that
`authors attributed to differences in the absorptive surface
`area [9].
`
`A mucoadhesive, buccal-soluble film (Meda Pharmaceu-
`ticals, Inc., Somerset, NJ) has also been approved in the
`United States using the BioErodible MucoAdhesive
`(BEMA™, BioDelivery Sciences, Inc., Raleigh, NC) delivery
`technology. Once applied to the oral mucosa, the fentanyl
`buccal soluble film (FBSF) (US: Onsolis®, Meda Pharma-
`ceuticals Inc.) adheres to the mucosa in seconds. Fenta-
`nyl is contained in the mucoadhesive layer, and a second
`inactive layer separates the fentanyl-containing layer from
`the saliva and limits the amount of fentanyl that is swal-
`lowed. Each film is composed of water-soluble polymers
`that completely dissolve so there is no residual product to
`be removed, and there is a direct proportional relationship
`between the surface area of the film and the administered
`dose.
`
`The objectives of this open-label, randomized, single-
`dose, crossover pharmacokinetic study were to determine
`the absolute bioavailability of fentanyl from this advanced
`transmucosal delivery system, estimate the percentage of
`a fentanyl dose that
`is absorbed through the buccal
`mucosa, and compare the bioavailability of equivalent
`doses administered either as single or multiple dose units.
`
`Methods
`
`This was an open-label, randomized, four-period, Latin-
`square crossover study. The study protocol was approved
`by a regional institutional review board, and the study was
`conducted in accord with the principles of the Declaration
`of Helsinki and the US Code of Federal Regulations (Title
`21, Part 50). All subjects read and signed an approved
`informed consent form during screening.
`
`Participants
`
`Subjects eligible for inclusion in the study were healthy
`adult male and nonpregnant, nonlactating female volun-
`teers aged 18–45 years, weighing 60–100 kg, and within
`15% of their ideal body weight based on Metropolitan Life
`tables for height and weight. Premenopausal women were
`required to use an acceptable method of birth control and
`to have a negative urine test for b-human chorionic gona-
`dotropin. Consumption of alcoholic beverages, caffeine-
`or xanthine-containing beverages, or foods or beverages
`containing grapefruit was prohibited from 48 hours prior to
`the first dose of study medication until discharge from the
`
`1018
`
`study. Use of tobacco or nicotine-containing products
`within 30 days of the first dose of study medication was
`also not allowed.
`
`Subjects were excluded if they had participated in an
`investigational drug study within the previous 30 days; had
`taken any nutritional supplement or any prescription or
`nonprescription medication (except acetaminophen or
`oral contraceptives) within 72 hours of the first dose of
`study medication; or had a positive drug screen for
`amphetamines, barbiturates, benzodiazepines, cannab-
`inoids, cocaine or opiates, or a positive ethanol breath
`test. A history of a serious medical condition, including
`glaucoma or a seizure disorder, and allergy or intolerance
`to narcotics were also grounds for exclusion.
`
`Trial Design and Procedures
`
`The subjects were assessed at a screening visit and con-
`fined to a phase 1 unit throughout the 12-day treatment
`period. The Latin-square crossover study design was
`used to minimize variability by ensuring each subject
`received a single dose for each treatment each period.
`Each subject received the following four study treatments
`on days 1, 4, 7, and 10: injectable fentanyl citrate 200 mg
`administered via an intravenous infusion pump over 5
`minutes; injectable fentanyl citrate 800 mg/16 mL admin-
`istered orally via a 20 mL oral syringe followed by 90 mL of
`water; fentanyl 800 mg as a single film applied to the
`buccal mucosa; and fentanyl 800 mg administered as four
`separate 200 mg films applied to the buccal mucosa within
`a 2-minute period. The 800 mg film provided a surface
`area that is four times larger than that of the 200 mg one
`(3.1 cm2 compared with 0.78 cm2). Each drug administra-
`tion was separated by a washout period of at least 72
`hours.
`
`A commercially available injectable fentanyl citrate product
`(Fentanyl Citrate Injection, Hospira, Inc., Lake Forest, IL;
`Lot 44-296-DK, Expiration August 1, 2008) was used for
`the intravenous and oral doses. The buccal dosage form
`contained fentanyl citrate, but the dosage is expressed as
`fentanyl free base.
`
`Prior to application of the buccal soluble film doses, the
`subjects rinsed their mouths with water. Buccal doses
`were placed on the mucosa inside the cheek below the
`level of the lower teeth. Each film was then applied to the
`mucosa and held in place for a few seconds until it was
`moistened by saliva and adhered to the mucosal mem-
`brane. The subjects were instructed not to rub the film
`with their tongue. With the four-film regimen (D), two films
`were applied to the posterior portion and two to the ante-
`rior portion of the contralateral sides of the mouth.
`
`All of the subjects received oral naltrexone 50 mg approxi-
`mately 12 hours and 1 hour prior to, and approximately 12
`hours after study drug administration to block the respi-
`ratory depressive effects of fentanyl in these opioid-naïve
`subjects. Predose procedures were performed on the
`evening of day 0 and the subjects received the study drug
`
`Page 2 of 7
`
`

`
`approximately 1 hour after consuming a standard light
`breakfast on days 1, 4, 7, and 10. The subjects fasted for
`4 hours after receipt of study medication.
`
`Blood samples for measurement of fentanyl plasma con-
`centrations were collected prior to drug administration (0
`hour) and at 5, 10, 15, 20, 30, 45, and 60 minutes, and 2,
`3, 4, 8, 12, 16, 20, 24, and 48 hours after each dose of the
`study drug. Pharmacokinetic sampling times began with
`the application of the first film when the subjects received
`the four-film regimen.
`
`Sample Collection and Pharmacokinetic Analysis
`
`Venous blood samples (7 mL) were collected in EDTA
`Vacutainer® tubes (BD, Franklin Lakes, NJ). Within 30
`minutes of collection, the samples were centrifuged and
`the plasma fraction removed and stored at -20°C pending
`analysis.
`
`Fentanyl concentrations in plasma were determined by a
`validated liquid chromatography with tandem mass
`spectrometry method that has a lower limit of quantifi-
`cation of 0.0250 ng/mL and an upper limit of quantifica-
`tion of 5.00 ng/mL. Fentanyl-D5 was used as the internal
`standard. Quantification was performed by a weighted
`linear least squares regression analysis that was
`(1/X2)
`generated from calibration standards. Bioequivalence
`between the 4 ¥ 200 mg and 1 ¥ 800 mg FBSF was
`determined by comparison of the 90% confidence inter-
`vals (CIs) for the log-transformed exposure parameters
`Cmax, AUClast, and AUCinf against the accepted 80% to
`125% range.
`
`The following pharmacokinetic parameters were calcu-
`lated: Cfirst = first measurable drug concentration in
`plasma determined directly from individual concentration
`time data; Cmax = maximum drug concentration in plasma
`determined directly from individual concentration time
`data; Tmax = time to Cmax; lz = observed elimination rate
`constant estimated by linear regression through at least
`three points in the terminal phase of the log concentration
`time profile for each subject; t1/2 = observed terminal elimi-
`nation half-life calculated as ln(2)/lz; AUC0–48 = area under
`the drug concentration time curve from time 0–48 hours
`calculated using the linear trapezoidal rule and extrapo-
`lated using lz if measurable plasma concentrations were
`not obtained throughout the 48-hour sampling period;
`AUClast = area under the drug concentration time curve
`calculated using linear trapezoidal summation from time
`zero to the time of the last measurable concentration;
`AUCinf = area under the drug concentration time curve
`from time zero extrapolated to infinity calculated as
`AUClast + Clast/lz.
`
`The absolute bioavailability of fentanyl was determined
`using the following equation:
`
`(
`
`=
`
`F
`
`(
`
`Dose
`extravascular
`
`)
`
`Dose AUC
`iv
`iv
`AUC
`extravascular
`
`=
`
`)
`
`∗ AAUC
`
`Dose
`iv
`Dose
`extravascular
`
`extravascular
`∗
`AUC
`iv
`
`Pharmacokinetics of Fentanyl Buccal Soluble Film
`
`Doseextravascular and AUCextravascular are those that pertain to
`oral or buccal administration. Mean AUCinf was used in
`these calculations. The percentage of the dose absorbed
`through the buccal mucosa was estimated by subtracting
`the AUCinf after oral administration from that after buccal
`administration, dividing by the AUCinf after buccal admin-
`istration, and multiplying by 100.
`
`Safety Assessments
`
`Safety monitoring was composed of physical examination,
`vital signs, 12-lead electrocardiogram, laboratory studies,
`and evaluation of subjects for adverse events and moni-
`toring of oxyhemoglobin with a pulse oximeter.
`
`Statistics
`
`Plasma concentration time data were analyzed by non-
`compartmental methods using WinNonlin® (Pharsight
`Corporation, Mountain View, CA). Pharmacokinetic calcu-
`lations were based on actual sampling times. The statis-
`tical analysis was performed using SAS version 8.2 (SAS
`Institute Inc., Cary, NC).
`
`Plasma fentanyl concentrations that were below the limit
`of quantification after drug administration were assigned a
`value of zero if collected prior to Cmax and were treated as
`missing values if collected after Cmax. For the subjects with
`measurable concentrations in predose samples, the first
`measurable concentration above the predose level after
`drug administration was redefined as the first measurable
`concentration.
`
`The sample size chosen for this study was based on
`conventional pharmacokinetic study designs, not a formal
`power calculation.
`
`log-transformed values for Cmax, AUClast, and
`Natural
`AUCinf were analyzed for differences between treatments
`and gender using an analysis of variance (ANOVA) model
`and Schuirmann’s two one-sided t-test procedures at the
`5% significance level, analogous to the analysis used for
`bioequivalence assessments; the ratio of the geometric
`means and the 90% CIs were reported [10].
`
`Values for Tmax after administration of a single 800 mg
`buccal film or four individual 200 mg films were compared
`with the Wilcoxon signed-rank test with a significant dif-
`ference defined as P < 0.05.
`
`Results
`
`A total of 12 subjects were enrolled, each of whom com-
`pleted all four treatment periods. A summary of the demo-
`graphic characteristics of the participants in the study is
`contained in Table 1. The mean age of the subjects was
`27 years, 50% were men, and 50% were black. Measur-
`able plasma concentrations of fentanyl were detected in
`predose (0 hour) samples collected for some of the sub-
`jects during periods 2, 3, and 4. The concentration of
`fentanyl in all such samples was <5% of the Cmax for the
`
`1019
`
`Page 3 of 7
`
`

`
`Vasisht et al.
`
`Table 1 Demographic characteristics
`
`Number of volunteers
`Male : female gender
`Mean age in years ⫾ SD (range)
`Race, n (%)
`Black
`Caucasian
`Hispanic or Latino
`Mean height in cm ⫾ SD (range)
`
`Mean weight in kg ⫾ SD (range)
`
`SD = standard deviation.
`
`12
`6:6
`27 ⫾ 6 (19–37)
`
`6 (50)
`4 (33)
`2 (17)
`169.0 ⫾ 9.0
`(154.5–180.5)
`70.7 ⫾ 6.4
`(63.0–84.1)
`
`profile in question, and as such, the concentrations were
`included in the analysis without adjustment.
`
`Single-Dose Pharmacokinetics
`
`The plasma concentration time profile of fentanyl admin-
`istered by the intravenous, oral, and buccal routes is illus-
`trated in Figure 1. The profiles for
`the two buccal
`treatments overlap very closely and are distinct from those
`for oral and intravenous administration.
`
`in each of the
`Pharmacokinetic parameters for fentanyl
`treatment periods are presented in Table 2. The mean Cmax
`of fentanyl was identical (1.33 ng/mL), and exposure as
`
`measured by mean AUCinf, was nearly identical (13.03 vs
`13.09 hours/ng/mL) after administration of the two buccal
`treatments (Table 2). Following the buccal doses, mean
`Cmax and AUCinf were 1.9 and 2.0 times that of oral admin-
`istration. The absolute bioavailability of fentanyl from the
`buccal soluble film treatments was 71%, which is approxi-
`mately double that after oral administration (35%). The
`percentage of an administered dose absorbed through
`the buccal mucosa was calculated to be 51%.
`
`Pharmacokinetic parameters were generally similar in the
`males and the females after administration of a single
`800 mg buccal dose of fentanyl (Table 3). The exception
`was the mean t1/2, which was longer in the females (15.6
`hours) than in the males (10.9 hours), a finding that may be
`attributable to particularly long half-lives in two individuals.
`When analyzed by ANOVA, the female : male ratios of the
`geometric mean values for Cmax, AUClast, and AUCinf were
`94.46%, 93.89%, and 102.5%, respectively. Due to the
`small sample size (i.e., six female and six male subjects),
`the power associated with these comparisons is low
`(0.44, 0.34, and 0.34, respectively).
`
`There were no differences in bioavailability in terms of
`either the rate or extent of absorption of fentanyl after
`administration by the buccal route as a single 800 mg film
`or as four 200 mg films (Table 4). The median Tmax
`occurred later after administration of
`fentanyl as four
`200 mg films compared with a single 800 mg film (2.5 vs
`1.5 hours, respectively), although the difference was not
`statistically significant (P = 0.0781 by Wilcoxon signed-
`rank test).
`
`1020
`
`Figure 1 Mean plasma con-
`IV = intrave-
`centration profile.
`nous; SD = standard deviation.
`
`Page 4 of 7
`
`

`
`Pharmacokinetics of Fentanyl Buccal Soluble Film
`
`Table 3 Statistical analysis of fentanyl plasma
`pharmacokinetic parameters in female and male
`subjects after administration of a single 800 mg
`fentanyl buccal soluble film
`
`Geometric LSM*
`
`Parameter
`
`Female
`
`Male
`
`Ratio of LSM for
`Female/Male, %
`
`ln Cmax
`ln AUClast
`ln AUCinf
`
`1.265
`10.693
`12.738
`
`1.337
`11.389
`12.483
`
`94.46
`93.89
`102.05
`
`* Values are the least squares means (LSMs). LSMs are the
`average of means associated with a treatment.
`AUCinf = area under the drug concentration time curve from
`time zero extrapolated to infinity; AUClast = area under the drug
`concentration time curve from time zero to the time of the last
`measurable concentration; Cmax = maximum observed plasma
`drug concentration.
`
`Safety
`
`No serious adverse events were reported during the
`study and no subject withdrew from treatment because
`of adverse events. A total of nine adverse events were
`reported by three subjects. All adverse events were con-
`sidered to be mild in intensity and all were resolved
`spontaneously. Contact
`dermatitis
`and menstrual
`cramps were reported after intravenous administration
`(N = 1 each); loose stool, nausea, and skin rash were
`reported after oral administration (N = 1 each); dizziness
`and headache were reported after buccal administration
`of a single 800 mg buccal film (N = 1 each), and consti-
`pation and headache were reported after administration
`four 200 mg buccal films (N = 1 each). No clinically
`of
`significant observations or changes in vital signs, physi-
`cal examinations, electrocardiograms, or clinical
`labora-
`tory tests were identified in the subject population during
`the study.
`
`Discussion
`
`Based on AUCinf estimates, this study showed that the
`bioavailability of FBSF was 71%, which was greater than
`the bioavailability after oral fentanyl (approximately 35%).
`As determined by pharmacokinetic calculation, the per-
`centage of the fentanyl dose absorbed through the buccal
`mucosa was estimated to be 51%. Overall systemic expo-
`sure as assessed by AUC and Cmax was nearly identical
`after administration of 1 ¥ 800 mg and 4 ¥ 200 mg FBSF.
`No differences in bioavailability were observed in the rate
`and extent of absorption between 1 ¥ 800 mg and
`4 ¥ 200 mg dosages, indicating that multiple small dose
`units can be used interchangeably with higher dose units.
`Furthermore, the pharmacokinetic profile of FBSF was not
`gender-dependent, with similar values for both males and
`females for the exposure parameters of Cmax, AUClast, and
`
`1021
`
`maximumplasmadrugconcentration;t1/2=eliminationhalf-life;lz=eliminationrateconstant.
`AUC=areaunderthedrugconcentrationtimecurve;Cmax=maximumobservedplasmadrugconcentration;CV=coefficientofvariation;SD=standarddeviation;Tmax=timeto
`Valuesarepresentedasarithmeticmeans⫾SD.
`
`18.29⫾4.14(22.61)
`2.50;1.00–4.00
`0.04⫾0.01(26.71)
`10.57⫾3.37(31.91)
`13.09⫾3.62(27.62)
`11.70⫾3.20(27.37)
`1.33⫾0.43(32.30)
`
`19.03⫾8.31(43.67)
`1.50;0.75–4.00
`0.042⫾0.016(37.32)
`12.23⫾6.77(55.35)
`13.03⫾3.45(26.50)
`11.40⫾3.03(26.57)
`1.33⫾0.31(23.01)
`
`13.26⫾5.68(42.80)
`3.00;1.00–4.00
`0.061⫾0.023(37.91)
`11.84⫾3.16(26.66)
`6.39⫾2.28(35.63)
`5.65⫾2.09(37.01)
`0.69⫾0.21(30.21)
`
`18.03⫾10.08(55.91)
`0.17;0.08–0.37
`0.052⫾0.032(60.96)
`17.75⫾5.44(30.63)
`4.62⫾1.51(32.76)
`3.78⫾1.18(31.16)
`1.46⫾0.66(44.97)
`
`Meant1/2⫾SD,hours(CV%)
`MedianTmax;range,hours
`Meanlz⫾SD,hours-1(CV%)
`MeanAUCextrap⫾SD,(CV%)
`MeanAUCinf⫾SD,hour/ng/mL(CV%)
`MeanAUClast⫾SD,hour/ng/mL(CV%)
`MeanCmax⫾SD,ng/mL(CV%)
`
`(4¥200mgFilms)
`D:Buccal
`
`(1¥800mgFilm)
`C:Buccal
`
`(800mgFentanylCitrate)
`B:OralAdministration
`
`(200mgFentanylCitrate)
`A:IVAdministration
`
`Parameter
`
`Table2Single-dosepharmacokineticsoffentanylafterintravenous,oral,andbuccaladministration
`
`Page 5 of 7
`
`

`
`Vasisht et al.
`
`Table 4 Exposure to fentanyl after administration of a single 800 mg fentanyl buccal soluble film or four
`200 mg fentanyl buccal soluble films
`
`Geometric LSM*
`
`Four ¥ 200 mg
`Films
`
`1.269
`11.283
`12.625
`
`Parameter
`
`ln Cmax
`ln AUClast
`ln AUCinf
`
`Single 800 mg
`Film
`
`1.301
`11.036
`12.610
`
`Ratio of LSM for
`4 ¥ 200 mg/800 mg, %;
`90% CI
`
`97.50;90.50–105.04
`102.24;96.61–108.21
`100.12;94.00–106.64
`
`ANOVA CV%
`
`9.83
`7.48
`8.32
`
`* Values are the least squares means (LSM).
`ANOVA = analysis of variance; AUCinf = area under the drug concentration time curve from time zero extrapolated to infinity;
`AUClast = area under the drug concentration time curve from time zero to the time of
`the last measurable concentration;
`CI = confidence interval; Cmax = maximum observed plasma drug concentration; CV = coefficient of variation.
`ANOVA CV% is the square root of the residual variance times 100.
`
`AUCinf. Adverse events with FBSF were mainly gas-
`trointestinal and central nervous system disorders that
`were mild in intensity and resolved spontaneously.
`
`The safety results we report here are similar to that of other
`formulations of fentanyl [11]. The lack of gender effects
`reported here is different
`from the results previously
`reported for the fentanyl buccal tablet, which reported a
`20% to 30% increased systemic exposure for females [4].
`
`In a comparative crossover study conducted in 26 volun-
`teers, the following absolute bioavailability ratios were
`reported: FBT, 65%; OTFC, 47%; and FBT administered
`orally, 31% [11]. Although the bioavailability reported here
`for FBSF (71%) is higher than that reported for FBT (65%),
`the clinical relevance of
`this cross-comparison is not
`known. The buccal absorption rate of 51% reported here
`is comparable with the 48% transmucosal absorption for
`FBT and more than two-fold higher than the 22% trans-
`mucosal absorption reported for OTFC [11].
`
`FBSF as examined in this study has distinct pharmacoki-
`netic properties in comparison with other commercially
`available fentanyl dosage forms intended for buccal
`administration. The study demonstrates that a buccal
`soluble film dosage form delivers fentanyl with high abso-
`lute bioavailability (71%) when administered as a single
`800 mg film or as four individual 200 mg films and that the
`two study treatments are bioequivalent.
`
`The high fentanyl bioavailability produced by FBSF results
`from the significant drug fraction that undergoes transmu-
`cosal absorption and therefore that escapes from first-
`pass metabolism. The effectiveness of
`transmucosal
`absorption, in turn, likely reflects the effectiveness of the
`film inactive layer in minimizing the amount of fentanyl that
`is swallowed with the saliva.
`
`The observed bioequivalence when the same dose is
`administered as a single film or four different films results
`from the fact that the absorption produced by buccal film
`
`1022
`
`technology is proportional to the surface area of the film.
`Consequently, the absorption surface area with a single
`800 mg film is exactly the same as with four individual
`200 mg films.
`
`The major limitation of the study is that it was conducted
`in healthy volunteers, who had to be given naltrexone to
`prevent respiratory depression. There may be differences
`in the pharmacokinetics of fentanyl as experienced by the
`patients with cancer, who may be undergoing chemo-
`therapy or may be taking multiple concurrent medications.
`However, because the dose is set individually by titration,
`any such differences are not likely to be clinically relevant.
`Another limitation is that the washout time was at least 72
`hours, which corresponds to 3.8 terminal half-lives.
`However, the residual concentration was <5% and was
`taken into account in the calculations.
`
`In conclusion, the absolute bioavailability of fentanyl from
`the buccal soluble film is determined in the present study
`to be 71%. The direct relationship between the surface
`area of
`the film and the dose of
`fentanyl
`results in
`bioequivalence between a single unit and that of multiple
`dose units that give the same combined total dose. This
`aspect provides confidence in the titration of FBSF to an
`effective dose for the management of breakthrough pain.
`
`Acknowledgments
`
`This study was funded by BioDelivery Sciences Interna-
`tional, Inc. Editorial assistance was provided by Blair J.
`Jarvis and Carol A. Lewis, PhD.
`
`References
`1 Caraceni A, Martini C, Zecca E, et al. Breakthrough
`pain characteristics and syndromes in patients with
`cancer pain. An international survey. Palliat Med
`2004;18:177–83.
`
`2 William L, Macleod R. Management of breakthrough
`pain in patients with cancer. Drugs 2008;68:913–24.
`
`Page 6 of 7
`
`

`
`3 Portenoy RK, Payne D, Jacobsen P. Breakthrough
`pain: Characteristics and impact
`in patients with
`cancer pain. Pain 1999;81:129–34.
`
`4 Zeppetella G, O’Doherty CA, Collins S. Prevalence
`and characteristics of breakthrough pain in cancer
`patients admitted to a hospice. J Pain Symptom
`Manage 2000;20:87–92.
`
`5 Zhang H, Zhang J, Streisand JB. Oral mucosal drug
`delivery: Clinical pharmacokinetics and therapeutic
`applications. Clin Pharmacokinet
`2002;41:661–
`80.
`
`6 Streisand JB, Varvel JR, Stanski DR, et al. Absorption
`and bioavailability of oral transmucosal fentanyl citrate.
`Anesthesiology 1991;75:223–9.
`
`7 Lee M, Kern SE, Kisicki JC, Egan TD. A pharmacoki-
`netic study to compare two simultaneous 400
`microg doses with a single 800 microg dose of oral
`
`Pharmacokinetics of Fentanyl Buccal Soluble Film
`
`fentanyl citrate. J Pain Symptom
`transmucosal
`Manage 2003;26:743–7.
`
`8 Darwish M, Tempero K, Kirby M, Thompson J. Phar-
`macokinetics and dose proportionality of
`fentanyl
`effervescent buccal tablets in healthy volunteers. Clin
`Pharmacokinet 2005;44:1279–86.
`
`9 Darwish M, Kirby M, Robertson P Jr, Hellriegel E,
`Jiang JG. Comparison of equivalent doses of fentanyl
`buccal tablets and arteriovenous differences in fenta-
`nyl pharmacokinetics. Clin Pharmacokinet 2006;45:
`843–50.
`
`10 Food and Drug Administration. Guidance for Industry:
`Statistical Approaches to Establishing Bioequivalence.
`Rockville, MD: Center
`for Drug Evaluation and
`Research; 2001.
`
`11 Darwish M, Kirby M, Robertson P Jr, Tracewell W,
`Jiang JG. Absolute and relative bioavailability of fenta-
`nyl buccal
`tablet and oral
`transmucosal
`fentanyl
`citrate. J Clin Pharmacol 2007;47:343–50.
`
`1023
`
`Page 7 of 7