Pharmacokinetic properties of fentanyl effervescent buccal tablets: A phase I, open-label, crossover study of single-dose 100, 200, 400, and 800 μg in healthy adult volunteers

Clinical Therapeutics/Volume 28, Number S, 2006

Pharmacokinetic Properties of Fentanyl Effervescent Buccal Tablets: A Phase I, Open-Label, Crossover Study of Single-Dose 100, 200, 400, and 800 lag in Healthy Adult Volunteers M o n a D a r w i s h , PhD1; M a r y Kirby, MS1; P h i l m o r e R o b e r t s o n , Jr., PhD2; W i l l i a m T r a c e w e l l , PhD2; a n d J o h n G. Jiang, P h D 3

1Department of'Clinical Pharmacology, Cephalon, Inc., Frazer, Pennsylvania; 2Department of Drug 5afe{y and Disposition, Cephalon, Inc., West Chester, Pennsylvania; and 3Department of'Biometrics, Cephalon, Inc., Frazer, Pennsylvania ABSTRACT Background: The fentanyl effervescent buccal tablet (FEBT) is designed to eilhance tile rate and extent of tile absorption of fentanyl, an opioid, through tile buccal inucosa. Objectives: The purposes of this study were to assess the dose proportionality of FEBT in healthy voltu> teers over tile potential therapeutic dose range (100800 pg) and characterize tile pharmacokinetic (PK) profile of 4 doses (100, 200,400, and 800 pg) of FEBT. Methods: T~zis Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii. Healthy adult volunteers with intolerance to opioids were randomly assigned to receive 1 of 4 single-dose sequences of FEBT: 100, 200, 400, and 800 pg (selected to encompass tile anticipated therapeutic dose range), with each successive administration separated by a washout period of ~7 days. Naltrexone hydrochloride (S0-mg tablet) was administered -15 and 3 hours before and 9 hours after FEBT administration to block opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentrations were measured from venous samples obtained over 72 hours after FEBT administration. Early fentanyl exposure was assessed using AUC from time 0 to 0.75 hour (the median Tm~X of tile reference dose [100 pg]) (AUCc~Tm~,). Adverse events (AEs) were monitored and recorded tbroughout the study by medically qualified personnel. Results: Thirty-two subjects (26 men, 6 women; mean [SD] age, 29.3 [7.2] years [range, 1 9 4 4 years]; mean [SD] weight, 74.7 [10.7] kg) were etarolled. Median Tm~~ was between 35 and 45 minutes after FEBT administration. AUC0~ and Cm= increased approximately linearly with increasing doses of FEBT. Mean May 2006

plasma fentanyl concentrations decreased from C ..... in a biexponential manner at the 100- and 200-gg doses and decreased in a triexponential manner at tile 800-pg dose. Despite tile triexponential decrease in the mean profile observed with the 400-pg dose, a biexponential &crease was observed in approximately half of tilt individual profiles. AUC0~m~,~ ranged from 0.09 n g . bhnL with the 100-pg dose to 0.52 n g . bhnL with the 800-gg dose. The most commonly reported AEs in rile 100-, 200-, 400-, and 800-pg dose groups were as follows: application-site erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subjects; and headache, 3, 2, 1, and 4 subjects. None of tile AEs were serious. Conclusions: In this study of rile dose proportionality of FEBT in healthy voltmteers, rile PK profile of FEBT was characterized by a high early systemic exposure of fentanyl (0.09-0.52 ng . b/mL). Dosedependent parameters (Cm~X and AUC) increased in an approximately dose-proportional mariner from 100 to 800 pg FEBT. (CIin Tber. 2006;28:707-714) Copyright © 2006 Excerpta Medica, Inc. This work was previouslypublished in abstrac~form: Darwish M, MessinaJ, Tempero K. Relative bioavailability and dose proportionality of a novel effervescent form of fentanyl in healthyvolunteers.Anesthesiolo~,. 2005;103:A790. Availableat: h~ P://www" asaabstratus"c° m/stra nds/asaabstrac~s/abstrac~" htm;jsessionid 0E021F123BAA6313802B30E8044FB14S?year 200S&index 6&absnum 1066. Accepted~r publicationMarch18, 2005.

doi:lOlO16/jdinthera200605 015 0149 2918/06/$1900

Printed in the USA Reproductionin wholeor part is not permitted CopyrightO 2006ExcerptaMedica,Inc 707

Clinical Therapeutics

Key words: analgesics, dose proportionality, dose response, fentanyl effervescent buccal tablet, pharmacokinetics.

INTRODUCTION

The fentanyl effervescent buccal tablet (FEBT) is a formulation designed to eilhance the rate and extent of die absorption of fentanyl through the buccal mucosa. Fentanyl is a highly lipid-soluble opioid with a history of use as an IV analgesic and anesthetic in surgical and postoperative procedures) Additional formulations have been developed to extend the use of diis opioid beyond inpatient and surgical cases) 8 The toxicologic and pbarmacologic effects and mechanisms of action of fentanyl are well cbaracterized. However, die rate and extent of absorption vary based on the formulation used. The purposes of this study were to assess die dose proportionality of FEBT in healthy volunteers over the potential therapeutic dose range (100-800 pg) and to characterize die pharmacokinetic (PK) profile of 4 doses (100, 200, 400, and 800 pg) of FEBT. (See companion article in diis issue, "Relative Bioavailability of die Fentanyl Effervescent Buccal Tablet (FEBT) 1080 pg Versus Oral Transmucosal Fentanyl Citrate 1600 pg and Dose Proportionality of FEBT 270 to 1300 pg: A Single-Dose, Randomized, Open-Label, 3-Period Study in Healthy Adult Volunteers" by Darwish et al, which examines FEBT doses up to 1300 pg and compares relative bioavailabilities of FEBT and oral transmucosal fentanyl citrate.)

SUBJECTS AND METHODS This Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii, from January 2005 to February 2005. The study protocol was approved by die Schulman Associates Institutional Review Board, Inc., Cinciimati, Ohio, and carried out in full accordance with the Good Clinical Practice: Consolidated Guideline. 9 Indusion and Exclusion Criteria

Eligible subjects were healthy male and female adult volunteers with intolerance to opioids and normal findizags on medical history, physical examination (height, weight, franie size, vital signs, and electrocardiography [ECG]), and dimcal laboratory tests (hematology, sertmi biochemistry, urinalysis, hepatitis B surface anti708

gen screezl, hepatitis C antibody screen, sertmi pregnancy test [for women]) widlin 2 weeks before eilrollment in the study. To be included, vohmteers also had to have negative results on screemng for cannabinoids and opioids and to report being tricotine- and tobaccofree for at least 12 months before eiarollment. Prescription and over-the-counter medications were prohibited 2 weeks before dosing and during the study (with the exception of hormonal contraceptives [for women], acetaaninophen, and ibuprofen). All volunteers provided written informed cotlsent before study initiation and were financially compensated for their participation.

Study Design Subjects were randomly assigned, using a computergenerated table of random numbers, to 1 of 4 singledose sequences of FEBT: 100, 200, 400, and 800 lag (selected to encompass the anticipated therapeutic dose range). Subjects received all 4 doses of study drug, with each successive aclmimstration separated by a washout period of >7 days. Subjects fasted overnight before study drug administration. Because the subjects in dlis study were not opioid tolerant, naltrexone hydrochloride (50 mg) was orally administered -15 and 3 hours before and 9 hours after each study drug administration to block the opioid receptor-mediated effects of fentanyl. Subjects were instructed to place FEBT between die cheek and gtmi above a molar tooth and to allow die tablet to dissolve for 10 minutes. If any portion of die tablet remained after 10 minutes, subjects were instructed to gently massage die cheek in die location of the tablet for 5 minutes. At 30 minutes after FEBT adininistration, subjects were permitted to drink 125 mL of water and swallow any remaining portion of the tablet. Subjects continued to fast for 4 hours after adininistration of study drug. For measurement of plasma fentanyl concentratioixs, blood samples were collected by site staff usiixg a venous catheter iiimiediately before and 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, and 60 minutes after administration of study drug, and by venipuncture at 75 and 90 minutes and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours after adininistration of study drug. Before each blood saanple was drawn, die line was flushed with saline to ensure patency, and 2 mL of blood was drawn and discarded. At each sampling time point, 4-mL blood samples were collected into Volume 28 Number S

M. Darwlsh et al. tubes contaimng potassitml EDTA, inverted 6 to 8 times to mix, and placed on water/ice @4°C) for 5 minutes to 1 hour before centrifugation at 1500g at 4°C for 15 minutes. Samples were stored at - 2 0 ° C for <10 weeks before assay. Plasma fentanyl concentrations were determined using a method of high-performance liquid cbromatography (HPLC) with tandem mass spectrometric detection validated by PPD Development, Rictmlond, Virgima. Samples were processed using liquid-liquid extraction, with evaporation of the extract to dryness and recotastitution of the residue in acetomtrile. Chromatographic separation was performed using reversed-phase HPLC, with multiple reaction motaitoring of the effluent. The quantitation range of the assay, validated by PPD Development, was 25 to 10,000 pg/mL. Interassay precision (%CV) was <7%, except at the lower limit of quantificatiota, at which it was 16.2%. Interassay accuracy ranged from 94.1% to 102.7%. No interference in the assay associated with endogenous species in plasma or naltrexone was fotmd.

Assessment of Pharmacokinedc Properties The primary PK parameters for the assessment of dose proportionality were AUC0~ and AUC from time 0 to the last time point at which at least 75% of the subjects within each of the dose groups had a measurable plasma fcntanyl concentration (AUCc<). The 8-hour sampling time was used to calculate AUC0~. Cmax, Tm~ , apparent plasma terminal elimination rate constant (~'z), mad associated tl/2 were calculated. The secondary parameters were AUCc~24 h, AUC0~2 h, AUC from time 0 to the time of the median Trnax of the 100-gg dose group (AUC 0 rn,~:e) [early fentanyl exposure), and AUC 0 t" AUCc~Tm~' was calculated post hoc, where T m j = 0.75 hour (the mediata Trn~ of the reference dose [100 gg]). PK values were generated with \~(TinNonlin Noncompartmental Analysis version 4.1.a (Pharsight Corporation, Palo Alto, Califorina) using the linear trapezoidal method.

Tolerability Analysis The investigator or a nurse momtored adverse events (AEs) usiug clinical laboratory tests (sertm~ biochemistry, hematology, and urinalysis); physical exatnination, including vital sign measurements (sitting blood pressure mad heart and respiratory rates); blood hemoglobin-oxygen saturation measurements; ECG; oral mucosal examination; mad concomitant

May2006

medication use. The oral mucosa at the site of the tablet placement was assessed 1 hour after study drug administration by the investigator or a medically qualified designee. After reports of AEs, subjects were closely observed until resolution of the AE.

Statistical Analysis Based on an intrasubject SD of 0.29, with an expected ratio of 1.05 estimated from data collected in a previous dose-proportionality study of FEBT in healthy subjects, 10 it was dcteriinned that a minimtml of 6 subjects per sequence (24 total) was necessary to provide >80% power to conclude dose proportionality using the bioequivalence approach. LogaritImltransformed (In)-AUC0~ , AUCc~¢, mad Cm~X were analyzed using a mixed-effects model. 11 Dose proportionality ftom 100 to 800 gg was assessed using a 90% CI on the slope (13) of the regression linell: ln(PK) = 0¢ + 13In[dose) + a where the random error term e was modeled to accotmt for both intrasubject and intersubject variatiom. Dose proportionality was concluded if the 90% CI about the fixed effect for slope (13) fell between 0.89 and 1.11. \~There 90% CIs for 13 fell partially in the interval, the results were considered nonconclusive, and the analysis was repeated with the ratios of dose-normalized means of paired doses, using the 100-pg dose as a reference. If 90% CI fell between 0.80 mad 1.25, dose proportionality was concluded. The results for Tm~Xwere assessed using the Wilcoxon raiak stun analysis. All other secondary parameters were stmmlarized by dose using descriptive statistics.

RESULTS Study Population A total of 32 subjects (26 men, 6 women; meatl [SD] age, 29.3 [7.2] years [range, 1 9 - 4 4 years]; mean [SO] weight, 74.7 [10.7] kg) were etarolled in the study and received >1 dose of study medication ]Table I). Subjects received FEBT at 100-pg (n = 31), 200-ug (n = 32), 400-pg (n = 32), and 800-pg (n = 32) doses. One subject withdrew from the study after completing 3 of 4 periods because of a moderate AE (periodontal abscess) unrelated to study medication, and was not included in the PK analysis set but was included in the tolerability analysis (N = 32). Estimates of )~ could not be obtained in some subjects because of incom-

709

Clinical Therapeutics

Table I. Demographic and baseline clinical charac teristics o f the study population (N 32).

Characteristic

Value

Age, y Mean (SD) Range

29.3 (7.2)

Sex, no. Male Female Weight, mean (SD), kg

19 44

26 6 74.7 (10.7)

Height, mean (SD), cm

175.4 (7.6)

BMI, mean (SD), kg/m 2

24.3 (3.2)

Ethnicity, no. White Asian Black Other* BMI

22 4 3 3

body mass index.

*lncludesAsian/Hispanic/Pacific Islander and white/Pacific Islander.

plete characterization of the terminal elimination period; therefore, parameters dependent on )~ 0% tlr2 and AUC0~) could not be calculated in these subjects.

Pharmacokinedc Properties The mean AUCs for each dose of FEBT are shown in Figure 1. The dose-independent median T ..... ranged from 35 to 45 minutes after FEBT adininistration; Cm~ ranged from 0.25 to 1.59 ng/mL AUC 0 rm~V ranged from 0.09 ng • b/mL with the 100-pg dose to 0.52 ng • MmL with the 800-pg dose. Absorption was followed by a biexponential decrease from Cm~X values at the lower doses (100 and 200 pg) and a triexponential decrease from Cm~ at the tfighest dose (800 pg). Although the mean PK profile with the 400-pg dose exIfibited a triexponential decrease, a biexponential decrease was observed in approximately half of the individual subject profiles. The PK properties of FEBT are stmmiarized in Table II. The median estimated ttr2 values increased with escalating doses and ranged from - 3 to - 1 2 hours. A dose-proportional increase in AUC0~ was found (Figure 2A, Table II), with the 90% CI of the slope of In(AUC0~) versus In(dose) (1.00-1.10) contained wit}> 710

in the dose-proportionality limits (0.89-1.11). The 90% CIs for die other dose-dependent parameters, including the slope of In(AUC 0 ¢) versus In(dose) (0.880.96), were not completely within the predetermined range, and therefore were not conclusive. These parameters mldcrwent further testing for the assessment of dose-normalized~ pairwise means using the 100-gg dose as t}le reference. Based on t}~is subanalysis, all dosedependent parameters, including AUC 0 t', increased in an approximately linear mazlner with each increase in dose (Figure 2B, Table II). Exceptions to the conclusion of dose proportionality were not specific to any pairwise comparison, and no cozlsistent trend toward deviation from proportionality was observed.

Tolerability Although AEs tbat occurred after naltrexone but before FEBT administration (constipation, dry mouth, fatigue, headache, nausea, and upper abdominal pain [1 subject each]) could be ascribed to naltrexone, those AEs occurring after FEBT a&ninistration could not be definitively attributed to FEBT or naltrexone. The most frequently reported AEs (ie, those reported in >5% of subjects at any dose) in the 100-, 200-, 400-, and 800-pg dose groups were as follows: applicationsite erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subiects; and h~adache, 3, 2, 1, and 4 subjects (Table III). The 6 cases of decreased oxygen saturation were considered of mild severity and resolved without intervention within 4 hours of onset, with no residual effects. Nine subjects experienced AEs considered of moderate severity (headache and nausea [2 subjects each], and dizziness, mouth ulceration, neck pain, tooth abscess, and vomiting [1 subject each]), and 21 subjects experienced AEs considered mild. Inspection of the oral mucosa found 10 subjects with AEs related to FEBT application site (eryr}lema and/or ulcer). All AEs related to the application site were considered mild and resolved within 3 hours to 9 days of onset, with no residual effects. N o serious AEs or deadis were reported during die study. DISCUSSION Given that the rate and extent of fentanyl absorption vary according to the formulation used, it is important to assess the PK properties of any new formulation, including FEBT. Because tiffs study involved healthy Volume 28 Number S

M. Darwlsh et al.

II

......... qOF FEBT 200 ug 41~ FEBT 400 ug

1.5

........

2 E

=a 0

I

2

3

4

u

oO 0

~ 10

20

30

40

Time After Study Drag Administration (h) Figure 1. Mean (SEM) AUCs in subjects receiving single dose administration of fentanyl effervescent buccal tablet (FEBT) (N = 32). The quantitation range of the assay, as validated by PDD Development, Richmond, Virginia, was 25 to 10,000 pg/mL Inset represents an expanded view (without error bars) of the first 4 hours after study drug administration.

subjects without tolerance to opioids, naltrexone was adininistered to block opioid receptor-mediated effects of fentanyl. In contrast, in a study of the PK properties and tolerability of transdemial fentanyl 100 pg/h coadininistered with oral naltrexone 100 mg in 24 healthy men, Lot et alt2 found that coadininistration of naltrexone with fentanyl did not appear to interfere with fentanyl's PK properties. The present study assessed the dose proportionality of 4 single doses (100, 2 0 0 , 4 0 0 , and 800 pg) of FEBT and found that dose-dependent parameters increased in an approximately linear mamler. The PK profile of FEBT was characterized by a r a p i d absorption (doseindependent median Tm~x, 3 5 4 5 minutes), and a high early systemic exposure to fentanyl (AUC0 r m ~ x " 0.09 n g . hhnL with die 100-pg dose to 0.52 n g . WmL with the 800-pg dose). Dose-dependent parameters (Cm~~ and AUC) were found to increase in an approximately dose-proportional manner. Although the 90% Ma.y 2006

CIs for some parameters did not fall within doseproportionality limits, exceptions suggested no trend toward deviation from linearity. The & d i n e in plasma fentanyl concentrations found in this study was consistent with die known PK profile of fentanyl, t3,t4 The initial portion of decrease represented a rapid distribution to die highly perfused tissues (eg, brain, heart, lungs), followed by gastrointestinal absorption/elinmlation of any fentanyl that had been swallowed. After gastrointestinal absorption, redistribution of fentanyl to die deep tissue compartment (nmsde and adipose tissue) and subsequent elinlination occtlr, t3,t4 The observed terminal tt/2 was representative of this elimination phase. The large range of median estimated tt/2 (-3 hours for the 100-pg dose to - 1 2 hours for the 800-pg dose) was attributable to the incomplete characterization of the terminal elimination phase, in which plasma concentrations at saanpling times later in the profile were not 711

Clinical Therapeutics

Table II. Pharmacokinetic properties o f single dose administration of fentanyl effervescent buccal tablet in healthy volunteers (n = 31 in each dose group unless otherwise specified). Property AUC 0 ~, mean (SD), ng. h/mL* AUC0 t', mean (SD), ng. h/mL AUC0 24 h, mean (SD), ng. h/mL AUC0 72 h, mean (SD), ng. h/mE AUC0~ma/, mean (SD), ng. h/mL AUC0 t, mean (SD), ng. h/mL Cm~ , mean (SD), ng/mL Tmax~ median (90% CI), h tl/2, median (90% CI), h* Ex[rapolation, mean (SD), %* ;Lz, l / h *

100 pg

200 pg

0.98 (0.37) 0.80 (0.26) 0.96 (0.41) 0.99 (0.46) 0.09 (0.06) 0.91 (0.42) 0.25 (0.1 4) 0.75

2.11 (1.13) 1.39 (0.46) 1.85 (0.80) 1.93 (0.90) 0.13 (0.09) 1.79 (0.82) 0.40 (0.18) 0.67

400 pg

800 pg

4.72 2.90 3.98 4.39 0.34 4.17

(1.95) (0.92) (1.37) (1.80) (0.23) (1.72) 0.97 (0.53) 0.58

9.05 (3.72) 5.27 (1.85) 7.38 (2.71) 8.39 (3.59) 0.52 (0.38) 8.11 (3.63) 1.59 (0.90) 0.67

(0.42 3.02)

(0.33 3.00)

(0.33 3.00)

(0.42 3.00)

2.63 (1.47 13.57) 15.17(4.98) 0.26(0.09)

4.43 (1.85 20.76) 15.28(6.90) 0.17(0.11)

11.09 (3.44 20.59) 11.74(4.51) 0.09(0.05)

11.70 (4.63 28.63) 10.13(5.36) 0.06(0.02)

AUC0 t' AUC from time 0 to the last time point ar which ar least 75% of subjects in each dose group had a measurable fen tanyl concentration; t" 8 hour sampling time; e)Crapolation % 100 X (AUG 0 ~ AUG0 t)/AUC0 ~ AUG 024 h AUG ~-om time 0 to 24 hours after study drug administration; AUC0 72 h AUG from time 0 to 72 hours after study drug administration; A U G 0 TrraZ AUG from time 0 to median Tr,~×for the reference dose (100 IJg); AUC0 t AUC from time 0 to the time of the last measurable fentanyl concentration; )~z apparent plasma terminal elimination rare constant. *n 25, 27, 29, and 30 subjects in the 100 , 200 , 400 , and 800 IJg groups, respectively.

A

B 6

E

8

/

E

6

R

/ v C

4

/,

/

3

R

/

/

/

/

/

Y

/

240

go

640

Dose (pg)

8~0

10'00

240

440

640

840

10100

Dose (pg)

Figure 2. Mean (SEM) (A) A U C 0 ~ and (B) AUC from time 0 to the last time point at which at least 75% of subjects in each dose group had a measurable fentanyl concentration (AUC0 t,) as a function of dose in subjects receiving single dose administration of fentanyl effervescent buccal tablet (N 32). The quantitation range of the assay measuring plasma concentrations of fentanyl, as validated by PDD Development, Richmond, Virginia, was 25 to 1 0,000 pg/mL.

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Volume 28 Number 5

M. Darwlsh et al.

Table ttt. Incidence ofadverse events (AEs) occurring in 25% ofsubjects receiving single dose ad ministration of fentanyl effervescent bua-al tablet (N = 32 in each dose group unless

otherwise specified).* Values are no. of subjects. AE

100 blgf

200 big

400 big

800 big

Application site erythema Nausea Somnolence Headache Decreased oxygen saturation Application site pain

3 3 3 3 3 2

3 2 2 2 2 0

4 5 3 1 1 1

3 4 2 4 3 0

Abdominal pain, upper Dizziness Fatigue Vomiting Pharyngolaryngeal pain Stomach discomfort Application site ulcer

1 1 1 1 0 0 0

2 1 1 0 4 2 1

1 2 1 1 1 0 2

4 2 3 3 0 0 4

19

21

18

21

No. of subjects with >1 AE

*Subjects were counted only once in each preferred term category. tOne subject withdrew fiom the study after completing 3 of 4 periods because of a moderate AE ( periodon tat abscess) unrelated to study medication, and was not included in the pharmacokinetic analysis set.

quantifiable for many subjects, particularly at lower doses. This difficulty in cbaracterizing the terminal phase of the curve also might explain the biexponendial decrease from Cm~X found at the lower doses compared with the triexponendial decrease found at the higher doses. Regardless, the final phase of elimination from the deep tissue compartment might have accounted for a small portion of the overall systemic exposure, and the PK tt/2 was not reflective of the duration of action of the drug. In general, FEBT and naltrexone were well tolerated. N o serious AEs or deaths were reported during the study. There were no clinically meaningful trends in changes from baseline to final assessment in serum biochemistry, hematology, vital sign measurements, ECG, or physical examination variables. Ten of 32 subjects reported AEs related to the application site (tablet placement) in this study. The incidence of application-site ulcers, but not erythema, might have been dose-dependent (FEBT 100 lag, 0 subject; 200 llg, 1; 400 llg, 2; and 800 lag, 4). However, all of the application-site AEs were considered of mild severity and resolved within a few hours or days after onset, with no residual effects. M a y 2006

MI studies employing an open-label design in healthy vohmteers are subject to limitations. Although this study used this design, it was adequately powered to determine dose proportionality from the 32 subjects enrolled in the study (n = 31 included in the PK analysis). Limitations inherent in an open-label design in healthy vohmteers include, but are not restricted to, the following: the PK profile derived from healthy subjects might not be representative of that in patients with medical conditions, particularly those associated with hepatic mlpairment, or in subjects receiving >1 concomitant medication likely to alter the metabolic pathway of the study drug. These confotmding factors are typically assessed in studies &signed to address these needs. CONCLUSIONS In this study of the dose proportionality of single-dose (100-800 llg) FEBT in healthy volunteers, the PK profile of FEBT was characterized by a high early systemic exposure of fentanyl. Dose-dependent parameters (Cm~X and AUC) increased in an approximately doseproportional manner in the 100- to 800-pg doses of FEBT studied in these volunteers, 713

Clinical Therapeutics

ACKNOWLEDGMENTS Jon L. Ruckle, M D , Radiant Research, Bellevue, Washington, was responsible for the subjects during the study. The authors tha*~: Anita P. Kuan, PhD; Meg A. Pahnatier, PhD; and Elizabeth A. Young, PhD (Envision Pharma, Inc., Southport, Connecticut) for their assistance in the manuscript preparation. REFERENCES 1. Stanley TH. Fentanyl. j Pain Symptom Manage. 2005;29 (Suppl S):$67 571. 2. Bennett D, Burton AW, Fishman S, et al. Consensus panel recommendations for the assessment and management of brealchrough pain: Part 2: Management. Pharm Ther. 2005; 30:3S4 361. 3. Mercadante S, Arcuri E, Fenera P, et al. Alternative treat ments of breakthrough pain in patients receiving spinal analgesics for cancer pain.] Pain Symptom Manage. 2005; 30:48S 491. 4. Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breab through cancer pain: A randomized trial comparing oral transmucosal fentanyl ciuate (OTFC) and morphine sul fare immediate release (MSIR). Pain. 2001 ;91:123 130. 5. Payne R. Ttansdermal fentanyl: Suggested recommenda tions for clinical use.jPainSymptom Manage. 1992;7(Suppl 3): $40 $44. 6. Mercadante S, Fulfaro F. Alternatives to oral opioids for cancer pain. Oncolo~,(IA411istonPark). 1999;13:215 220,225.

7. Rees E. The role of oral transmucosal fentanyl citrate in the management ofbrealchrough cancer pain. Intj Palliat Nuts. 2002;8:304 308. 8. Zeppetella G. Sublingual fentanyl citrate for canceFrelated brealchrough pain: A pilot study. Palliat Med. 2001;15: 323 328. 9. European Agency for the Evaluation of Medicinal Products, International Conference on Harmonisation World Health Organization. Guideline for Good Clinical Practice [EMEA Web site]. ICH Topic E6. Geneva, Switzerland: WHO; 2002. Available at: http://www.emea. eu.int. Accessed April 13, 2006. 10. Darwish M, Tempero K, Kirby M, Thompson J. Pharma cokinetics and dose proportionality of fentanyl efDrves cent buccal tablets in healthy volunteers. Clin Pharma cokinet. 200S;44:1279 1286. 11. Smith BP, Vandenhende FR, DeSante KA, et al. Confl dence interval criteria for assessment of dose proportion ality. PharmRes. 2000;17:1278 1283. 12. Lor M, Di Marco M, Marier J, et al. Pharmacokinetics, safety and tolerability of a novel 100 Dg/h transdermal fentanyl patch co administered with 100 mg oral naltrex one in healthy males. Clin PharmacolTher. 2005;77:P76. 13. Hug CCJr, Murphy MR. Tissue redistribution offentanyl and termination of its effects in rats. Anssthssiolo~,. 1981 ;SS: 369 37S. 14. Hudson RJ, Thomson IR, Cannon JE, et al. Pharmaco kinetics offentanyl in patients undergoing abdominal aor tic surgery. Anesthesiolo~. 1986;64:334 338.

Address correspondence to: Mona Darwish, P[fl3, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355. E-mail: [email protected]

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