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Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1080 pg versus Oral transmucosal fentanyl citrate 1600 pg and dose proportionality of FEBT 270 to 1300 μg: A single-dose, randomized, open-label, three-period study in healthy adult volunteers
Clinical Therapeutics/Volume 28, Number S, 2006
Relative Bioavailability of the 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, Three-Period Study in Healthy Adult Volunteers Mona
Darwish,
Jeffrey Thompson,
PhD1; Kenneth Tempero,
M D , P h D 2 ; M a r y Kirby, MS1; a n d
MS, MBA 2
l Cepkalon, Inc., Frazer, Pennsylvania; and 2CIMA Laboratories, Eden Prairie, Minnesota ABSTRACT
Background:The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain. Objectives: The primary objective of this study was to compare the relative bioavailability of FEBT 1080 lag with that of oral transmucosal fentanyl citrate (OTFC ®) 1600 lag, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1300 lag in healthy adult volunteers. Methods: This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1080 lag followed by single-dose OTFC 1600 lag, or vice versa; in period 3 (doseproportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1300 lag. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 lag, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For toleraMay 2006
bility analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed. Results:A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC0~ ) was statistically similar between FEBT 1080 lag and OTFC 1600 lag (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng. h/mL). However, the mean (SD) Cm= with FEBT 1080 lag was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1600 lag (P = NS), and the Tn~x of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC 0 Tma~; ie, AUC from time 0 to 1 hour [the median T of the reference dose of FEBT [810 lag]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] n g . h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC0~ and A U C 0 ~ , over the range of FEBT 270 to 1300 lag. Itlis workwas previously published in abstract form: Darwish M, Messina J, Tempero K. Relative bioavailability and dose pro portionality o f a novel effervescent form o f fentanyl in healthy volunteers. Anesthesiolo~. 2005;103:A790. Available at: http:// www'asaabstracts'c° m/stran ds/asaabst racts/abst ract'h t m ; jsessionid 0E021F123BAA6313802B30Eg044FB145?year 2005 &index 6&absnum 1066.
AcceptedforpublicationMarch29, 2006. doi:10.1016/j.clinthera.2006.05.016 0149 2918/06/$19.00 Printed in the USA.Reproduction in wholeor part is not permitted. Copyright© 2006 ExcerptaMedica,Inc. 71 S
Clinical Therapeutics Increases in Cn~x were less than dose proportional at FEBT doses >810 lag. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects], nausea (1 [2%]], upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT. Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC. Conclusions: In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1300 lag, whereas doses above 810 lag showed a less-than-doseproportional increase in Cn~x. The results suggest that fentanyl enters the systemic circulation to a significantly greater extent ( C ~ and AUC0~max,) and significantly more rapidly ( T ) with FEBT compared with OTFC. (Clin Ther. 2006;28:715-724) Copyright © 2006 Excerpta Medica, Inc. Key words: fentanyl, fentanyl effervescent buccal tablet, oral transmucosal fentanyl citrate, pharmacokinetics, effervescence.
INTRODUCTION Fentanyl is a well-studied, highly lipophilic, p-opioidreceptor agonist used as an anesthetic and analgesic. 1,2 Fentanyl effervescent buccal tablet (FEBT), a formulation designed for rapid absorption through the buccal mucosa,3,4 is being investigated for the management of breakthrough pain. At the site of administration, FEBT produces an effervescence reaction that liberates carbon dioxide, which becomes carbonic acid in solution. The reaction causes a decrease in pH, followed by the release of sodium carbonate, which increases pH. This decrease and increase in pH are hypothesized to optimize dissolution and membrane permeation, respectively, of fentanyl, facilitating rapid absorption through the buccal mucosa.3 s This rapid absorption might decrease the time to onset of analgesia suitable for the management of breakthrough pain. 716
The primary objective of this study was to compare the relative bioavailabilities of single-dose FEBT 1080 lag and oral transmucosal fentanyl citrate (OTFC ®) 1600 lag in healthy volunteers. OTFC was chosen as the comparator for the pharmacokinetic (PK) profile of FEBT because it uses a transmucosal delivery system. 7 A secondary objective was to assess the dose proportionality of FEBT at doses up to 1300 lag,which includes doses higher than those previously studied (_<800 lag).s (See the companion article in this issue, "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," by Darwish et al.) SUBJECTS A N D METHODS This randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. The study protocol was approved by the institutional review board (IRB) at MDS and carried out in full accordance with the Good Clinical Practice: Consolidated Guideline. 9 Inclusion and Exclusion Criteria Eligible volunteers were men and women aged 19 to 55 years who were non-opioid tolerant, with normal findings on medical history, physical examination (height, weight, frame size [normal weight was defined as -+15% of the ideal weight for height and estimated frame size1°], vital signs, and electrocardiography [ECG]), and clinical laboratory analysis (hematology, serum chemistry, urinalysis, HIV antibody screen, hepatitis B surface antigen screen, hepatitis C antibody screen, and serum pregnancy [women]) within 21 days before study enrollment, and reported to have been nicotine- and tobacco-free for 26 months before enrollment. Volunteers with positive results on screening for cannabinoids and/or opioids were exclude& All volunteers read and signed an IRB-approved informed-consent form before study procedures were performed and were financially compensated for their participation. Study Design Bioavailability was assessed in the first 2 administration periods of the study. Eligible subjects were randomly assigned, using a computer-generated randomization scheme, to 1 of 2 administration sequences: single-dose FEBT 1080 lag followed by single-dose Volume 28 Number S
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OTFC 1600 pg, or vice versa. The third period of the study employed a parallel-group design in which subjects were re-randomized to receive a single dose of FEBT 270, 810, or 1300 pg. Each study period was separated by a 7-day washout period (Figure 1). Over-the-counter medications were prohibited for 7 days before and during the study. Prescription medications were not allowed for 14 days before and during the study (with the exception of hormonal contraceptives for women). Subjects were asked not to consume any alcohol-, broccoli-, citrus-, caffeine-, or xanthine-containing foods or beverages for 48 hours before and during each study period. Strenuous physical activity was not allowed during the study. Study D r u g Administration and Pharmacokinetic Assessment Subjects arrived at MDS on the day before study drug administration. Standardized meals were provided, and subjects fasted for - 1 0 hours before study
drug administration on the following morning. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. If after 10 minutes a portion of the tablet remained, subjects were instructed to gently massage the cheek in the location of the tablet until it completely dissolved. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes (in accordance with the package insert11). If the OTFC lozenge did not dissolve completely after 15 minutes, it was allowed to continue to dissolve and the time to complete dissolution was recorded. Subjects were asked to remain seated for 4 hours after fentanyl administration, during which water intake was prohibited. Subjects were observed for 36 hours after fentanyl administration. Because subjects were not opioid tolerant, naltrexone hydrochloride, an opioid antagonist, was admin-
Healthy subjects screened <21 Days Subjects meeting inclusion criteria and undergoing randomization (N 42)
FEBT 1080 IJg (n 21) v OTFC 1600 ,ug (n 21)
OTFC® 1600 IJg (n 21)
7 Day washout
v FEBT 1080 ,ug (n 19)
Period 1
Period 2
Second randomization
(n 39) 7 Day washout
FEBT270 #g (n 14)
FEBT810 #g (n 13)
FEBT1300 #g (n 12)
Period 3
Figure 1. Study design. FEBT = fentanyl effervescent buccal tablet; OTFC = oral transmucosal fentanyl citrate.
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Clinical Therapeudcs istered to block the opioid receptor-mediated effects of fentanyl. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 lag, who were not given naltrexone at 12 hours because of the low dose they were receiving. Venous blood samples (7 mL) were collected at the following times in subjects receiving FEBT 810, 1080, or 1300 lag, or OTFC 1600 lag: before (time 0; baseline) and 10, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hours after study drug administration. In subjects receiving FEBT 270 lag, venous blood samples (7 mL) were collected before (time 0; baseline) and 10, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20, and 24 hours after study drug administration. Blood samples were collected by venipuncture into 7-mL tubes with no additive. Samples were allowed to clot at room temperature, centrifuged (2400 rpm at 4°C for 15 minutes), and stored at -20°C until analyzed. Serum concentrations of fentanyl were determined by MDS Pharma Services using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS). Internal standard, D-5fentanyl, was added and the analyte was extracted from human serum using liquid-liquid extraction under basic conditions. The linear range for the assay was 50.0 to 5000.0 pg/mL, with a limit of quantitation of 50.0 pg/mL. The method has reported selectivity against naltrexone up to concentrations of 10 ng/mL. Stability of fentanyl has been demonstrated in serum stored at -20°C for 32 weeks and stored at room temperature for 24 hours. The assay was considered accurate at CV _<7.89%. No interference in the assay was produced either by endogenous species in serum or by naltrexone. Concentrations less than the quantifiable limit of 50.0 pg/mL were recorded as 0. Tole rability Analysis For tolerability analysis, vital signs (sitting blood pressure, heart and respiratory rates) were measured each morning before study drug administration (time 0; baseline), at 15-minute intervals for 4 hours after administration, and at 5, 6, 8, 10, 24, and 36 hours after administration. Continuous pulse oximetry was conducted for the first 8 hours after dosing. At the screening visit and the conclusion of the study, a 12-lead ECG; clinical laboratory analysis (hematology, serum chemistry, and urinalysis); and physical examination, 718
including vital-sign measurements, were performed. Clinical laboratory tests were performed at MDS Pharma Services Clinical Laboratory, an accredited laboratory facility. Quality control material was run with each batch of samples (for serum chemistry tests), once per shift (for hematology tests), or every 24 hours (for urinalysis). Automated equipment was used to measure the vital signs of each subject. A blood pressure machine with oxygen saturation measurement capabilities (Critikon, GE Healthcare, Giles, United Kingdom) was attached to each subject's finger and connected to the automated equipment. Oxygen saturation was continuously monitored for 8 hours after study drug administration. Limits set for monitoring were within the range of 90% to 100% oxygen saturation. Subjects were instructed to inform the physician and/or nurses of any adverse events (AEs) that occurred during the study. To assess the effects of oral transmucosal delivery, each subject's oral mucosa was inspected for sores in the area of drug application at the beginning of each study period. Four hours after administration, subjects were asked how the area of drug application felt. The area was also inspected by a nurse, w h o recorded the subjects' answers and the results of the assessments.
Statistical Analyses The study was designed to enroll 42 volunteers for - 9 2 % power to assess relative bioavailability of FEBT and OTFC using a bioequivalence approach. 12,13 The sample size was not powered to assess dose proportionality; therefore, all dose-proportionality analyses in this study are exploratory. The dose-proportionality portion of the study was partly conducted in parallel. All of the subjects received FEBT 1080 lag in the relative bioavailability portion of the study (compared with OTFC 1600 lag). Subsequently, subjects were randomized to 1 of 3 groups and each group received one of the remaining FEBT doses (270, 810, or 1300 lag) in a parallel-group design. PK data from all 4 FEBT groups (270, 810, 1080, and 1300 lag) were used in the assessment of dose proportionality. The PK parameters--Cn~x, Tn~x, terminal elimination rate constant (Kel), elimination half-life (tl/2) , AUC04 , AUC0~ , AUC04/AUC0~ ratio, and AUC from time 0 to time of m a x i m u m concentration of fentanyl (AUC 0 T ~ x ) - - w e r e computed from the fentanyl concentration- time data for each dose. Early systemic exposure (AUCTmaf; ie, AUC from time 0 to 1 hour [the Volume 28 Number S
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median T of the reference dose, FEBT 810 lag]) was calculated post hoc, using noncompartmental methods. The relative bioavailability of FEBT 1080 lag versus OTFC 1600 lag was assessed using a bioequivalence approach. A parametric (normal theory) general linear model was applied to the logarithm (ln)-transformed C ~ , AUC04, and AUC0~ values. The multivariate analysis of variance (ANOVA) model included the following factors: sequence, subject within sequence, period, and drug administration. The two 1-sided hypotheses were tested at the 5% level for C ~ o AUCc~t, and AUC0~ by constructing 90% CIs for the mean ratios of FEBT 1080 lag to OTFC 1600 lag. Bioequivalence was concluded if the calculated CI fell within 80% to 125% of the ratio. 12 Differences in T ~ for the administration of FEBT 1080 lag and OTFC 1600 lag were assessed using the Wilcoxon signed rank test (c~ = 0.05). To explore the dose proportionality of FEBT, a general linear model was applied to dose-normalized Cm= and AUC parameters. The dose-by-group interaction was not significant for 2 of the 3 parameters ( C ~ and AUCc~t) , and the model was reduced to a 1-way ANOVA with the factor of dose. When an overall dose effect was found, pairwise comparisons were performed using the 1080-1Jg dose of FEBT as the reference because all subjects had received this dose. An additional analysis of dose proportionality from 270 to 1300 lag was performed using a 90% CI on the slope, [3, of the regression line: ln(PK) = c~ + [3In(dose) + e where the random error term e was modeled to account for both intrasubject and intersubject variation. A mixedeffects model was implemented to provide a 90% CI for the fixed effect of [3. If the CI fell completely within the limits (0.8580-1.1420), dose proportionality was concluded. 13 SAS version 6 (SAS Institute Inc., Cary, North Carolina) was used in the statistical analysis. RESULTS Study Population A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Two subjects withdrew after receiving 1 dose of OTFC (1600 ~g) in period 1 (1 for personal reasons, 1 for receiving an antibiotic); data from these subjects were excluded from the relative-bioavailability and doseMay2006
proportionality analyses. A third subject withdrew for personal reasons before beginning period 3; the data from this subject were included in the relative bioavailability analyses but not the dose-proportionality analysis. Post hoc analyses confirm that exclusion of the first 2 subjects mentioned did not affect the results of the relative-bioavailability analysis, and that the exclusion of data from all 3 subjects did not affect the results of the dose-proportionality analysis. A demographic summary of subjects is provided in Table I. Pharmacokinetic Properties AUCs for FEBT 270-, 810-, 1080-, and 1300-~g doses are shown in Figure 2, and the PK parameters of FEBT doses are shown in Table II. Mean serum fentanyl concentrations exhibited a bi- or triexponential decline from Cn~x, depending on how well the terminal portion of the curve was characterized. The range of tl/2 values was 6.6 to 13.2 hours (Table II). Tn~x values were comparable among FEBT 270-, 810-, and 1080-~g doses (median, 0.9-1.2 hours) and were longer after administration of the 1300-~g dose (median, 1.5 hours).
Table I. Demographic and baseline clinical characteristics of the study subjects (N = 42). Characteristic
Value
Age, y Mean (SD) Range
27 (11) 19 55
Sex, no. Female Male Race, no. White Asian European/Middle Eastern Hispanic Native American
25 17 33
4 2 2 1
Weight., mean (SD), kg
68.4 (8.7)
BMI, kg/m 2 Mean (SD) Range
23.1 (2.4) 18.8 28.3
BMI
bodymass index.
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FEBT270pg(n . ~ FEBT810pg(n FEBT1080pg (n FEBT1300pg(n
14) 13) 40) 12)
3.0
2.5 2.0
~" E
2.5
1.5
v ~
1.0 2.0
0.5
c
0
= o U
1.5
~
1.o
0
2
4
6
8
28
30
10
12
£ E
o;~ 0
2
4
6
8
10
12
14
16
18
20
22
24
26
32
34
36
Time Afrer Study Drug Administration (h) Figure 2. Mean (SEM) serum drug concentrations after administration of fentanyl effervescent buccal tablet (FEBT) 270, 810, 1080, and 1300 IJg. Inset is an expanded view (with no error bars) o f the first 12 hours after administration of FEBT.
Table II. Dose-proportionality evaluation: Pharmacokinetic (PK) properties offentanyl effervescent buccal tablet as measured in serum. Values are mean ( S D ) .
PK Proper~ C .... ng/mL Tm~ , h AUC0 t, ng" h/mL AUC0~ , ng" h/mL AUC 0 r/AUC 0 ~ ratio AUC0~ .... ng" h/mL tl/2, h Dose normalized values Cma~dose , pg" pg/mL* AUC 0 r/dose, pg" h/mL/pg AUC0~/dose , pg" h/mL/pg
270ug (n 14)
810ug (n 13)
1080 ug (n 40)
1300 ug (n 12)
0.8 (0.3) 1.2 (0.6) 4.3(1.6) 4.2 (1.7) 0.87 (0.04) 1.1 (0.4) 6.6(3.2)
2.6 (0.8) 0.9 (0.4) 15.3(4.3) 16.8 (4.4) 0.91 (0.04) 3.7 (1.0) 11.7(4.7)
2.7 (0.9) 1.1 (0.6) 16.5(5.5) 17.7 (5.4) 0.92 (0.0S) 3.8 (1.3) 11.7(5.0)
2.8 (0.9) 1.5 (1.0) 18.9(6.5) 21.0 (7.3) 0.91 (0.07) 4.0 (1.3) 13.2(7.7)
3.0 (1.2) 16.1 (5.9) 15.6 (6.5)
3.3 (1.0) 18.9 (5.3) 21.0 (5.5)
2.5 (0.8) 15.5 (5.0) 17.0 (5.0)
2.1 (0.7) 14.6 (5.0) 16.2 (5.7)
AUC0 Tmax= AUC from time 0 to time of maximum concentration of fentanyl. *P = 0.013 (analysis of variance of logarithm transformed dose normalized Crrax values).
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Relative Bioavailability The PK parameters obtained with FEBT 1080 pg and OTFC 1600 pg are shown in Table IlL Total systemic exposure (as measured using AUC0~ ) was statistically similar between these 2 study drugs (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng. h/mL). The estimated mean FEBT/OTFC ratios for AUC04 and AUC0~ were 1.014 and 1.011, respectively. The CI values for these ratios fell within the pre-established criterion for bioequivalence. Eased on the C ratio of 1.23 (90% CI, 1.118-1.362) for FEBT/OTFC, the 2 formulations did not meet the criterion for bioequivalence at the administered dose strengths because the upper 90% confidence limit of the C ~ ratio exceeded the upper limit for bioequivalence. Administration of FEBT also yielded higher early systemic exposure of fentanyl compared with OTFC administration, as measured using median T (1.0 vs 2.0 hours; P < 0.001) and mean (SD) A U C 0 ~ x, (1.5 [0.5] vs 0.8 [0.4] ng. h/mL; P < 0.001) (Figure 3 and Table III).
Analysis of the slopes of ln(Cn~x), In(AUC04), In(AUC0~), and In(AUCc~Tmag) versus In(dose) is shown in Table IV. This analysis found that fentanyl exposure, as determined by C ~ , increased in a less-thandose-proportional manner. The less-than-proportional increases in C ~ were offset by more sustained serum concentrations around the peak. This resulted in proportional increases in overall systemic exposure (as determined by AUC0~ ) that were linear over the range of 270 to 1300 pg (90% CIs for this parameter were completely contained within the critical range required for dose proportionality [0.8580-1.1420]). As noted above, T ~ x was comparable among FEET 270-, 810-, and 1080-pg doses and was slightly longer with FEET 1300 pg. Comparable tl/2 values were seen with the FEET 810-, 1080-, and 1300-pg doses. However, the tl/2 of the 270-pg dose was lower by -50% compared with the other 3 doses because the serum fentanyl concentration was less than the limit of detection at the terminal portion of the curve in 10 (71%) of 14 subjects who received this dose.
Dose Proportionality Dose-normalized total fentanyl exposures were comparable across FEET 270-, 810-, 1080-, and 1300-pg doses (AUC0 t/dose , range, 14.6-18.9 pg . h/mL/pg; AUC0 /dose , range, 15.6-21.0 pg. h/mL/pg; Table II). An initial ANOVA of the (In)dose-normalized C ~ values to assess dose proportionality found an overall dose effect (P = 0.013) (Table II). Therefore, pairwise comparisons of dose-normalized Cn~ were analyzed using the 1080-pg FEET dose as a reference; a difference was found only between FEET 810- and 1080-pg doses (P = 0.018).
Tolerability Definitive attribution of AEs to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone (to block opioid receptor-mediated effects). With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, vomiting, lightheadedness), and most (89.6%) were mild. No se-
Table III. Relative bioavailability assessment: pharmacokinetic properties o f fentanyl effervescent buccal tablet (FEB]-) and oral transmucosal fentanyl citrate (OTFC ~) as measured in serum (n = 40). Values are mean (SD) unless otherwise specified. Cmax~ ng/mL
ng ~ h/mL
AUCo ~, ng ~ h/mL
FEBT 1080 IJg
2.7(0.9)
16.0(5.5)
18.0(5.4)
1.5(0.5)*
1.0(0.3 2.0)*
OTFC 1600 Hg
2.2(0.7)
17.0(6.5)
18.0(7.1)
0.8(0.4)
2.0(0.8 4.0)
1.234 (1.118 1.362)
1.014 (0.944 1.089)
1.011 (0.936 1.092)
FEBT:OTFC ratio, ....... (90% CI)f
AUCo t,
AUCo~mJ, ng ~ h/mL
Tmax, Median (range), h
AUC0~ma/ AUC from time 0 to 1 hour (the median Tma×of the reference dose of FEBT [810 ~lg]). *P < 0.001 versus OTFC. fFEBT:OTFC ratio exponential (test reference) for logarithm transformed parameters.
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30
I
FEBT1080 pg(n = 40) OTFC 1600 pg(n = 40) 2.5
2.0
2 E
2.5
1.5 1.0
2.0
0.5
~: c
;
° 0
1.5
;
110
112
1.0
E o.s
0 -~T 0
2
q 4
T 6
q 8
T 10
F 12
T 14
F 16
T 18
F 20
q 22
g 24
q 26
T 28
q 30
T 32
q ~ 34 36
T i m e A f t e r S t u d y D r u g A d m i n i s t r a t i o n (h)
Figure 3. Mean (SEM) serum drug concentrations after administration of fentanyl effervescent buccal tablet (FEBT) 1080 pg or oral transmucosal fentanyl citrate (OTFC ~) 1600 pg. Inset is an expanded view (with no error bars) of the first 12 hours after administration of FEBT or OTFC.
Table IV. Dose-proportionality assessment using the fixed effect for slope (n = 40). Parameter
Slope (90% CI*)
In(Crrax)
0.8673 (0.7991 0.9356)
In(AUC0t)
0.9634 (0.9061 1.0206)
In(AUCo~ )
0.9376 (0.8697 1.0054)
In(AUC0~rcat )
0.9400 (0.8518 1.0283)
In logarithm transformed; AUC0~ma~ AUC fiom time 0 to 1 hour (the median Trr~xof the reference dose offentanyl effervescent buccal tablet [810 I]g]). *90% CI within the critical range of 0.8580 to 1.1420 is consistent with dose proportionality.
rious AEs were observed. One case each of mild oral irritation and redness were reported after the administration of FEBT. Both occurrences resolved within 4.5 hours. N o oral irritation or redness was reported after the administration of OTFC. 722
DISCUSSION A lower dose (1080 lag) of FEBT produced a total systemic fentanyl exposure (AUC0~) comparable with a higher dose (1600 lag) of O T F C in this PK comparison in these healthy volunteers. Early systemic fentanyl exposure (as measured by AUC0~n~ x, and C x) was proportionally greater (88% and 2 3 % , respectively) and occurred significantly earlier (as measured by T ~ x ) with FEBT compared with O T F C (P < 0.001). Both drugs were well tolerated, although attribution of AEs to either fentanyl formulation was confounded by the concomitant administration of naltrexone. The exploratory assessment of close proportionality suggests that FEBT was close proportional across the range of 270 to 1300 lag based on total systemic exposure of fentanyl (AUC0~), but increases in C ~ with FEBT at doses higher than 810 lag were less than proportional. At the lowest dose of FEBT (270 lag), the serum concentration was less than the lower limit of detection at the terminal portion of the curve in most (71%) subjects, which prohibited the accurate Volume 28 Number S
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characterization of the terminal portion of the curve at this dose and might have affected the calculation of tl/2 with this dose. OTFC is the first and only medication specifically approved in the United States for the treatment of cancer-related breakthrough pain in opioid-tolerant patients. 14 The effervescence delivery system of FEBT alters the PK profile of fentanyl in a way that might offer advantages over the noneffervescent OTFC formulation. Comparable total systemic fentanyl exposure (AUC0~) of FEBT 1080 lag and OTFC 1600 lag (mean FEBT:OTFC ratio, 1.011) suggests that a dose of FEBT would result in greater systemic exposure to fentanyl compared with a lag-equivalent dose of OTFC. The AUC0 Tn~x"was significantly greater with FEBT 1080 lag compared with OTFC 1600 lag (P < 0.001), reflecting the rapid entry of FEBT into the systemic circulation. Whether these PK differences would result in clinically meaningful differences between FEBT and OTFC needs confirmation in controlled clinical studies of patients with breakthrough pain. Transmucosal absorption allows fentanyl to bypass first-pass cytochrome P450 (CYP) 3A4-mediated gastrointestinal and/or hepatic metabolism. Thus, increasing the proportion of the dose undergoing transmucosal absorption allows more fentanyl to enter the systemic circulation compared with the gastrointestinal absorption of an equivalent amount of swallowed fentanyl. 3,4,n Seventy-five percent of the fentanyl from OTFC is swallowed and absorbed gastrointestinally, and is thus subject to CYP3A4-mediated first-pass metabolism in both intestinal and hepatic microsomes. 4 The formulation of FEBT may enhance absorption of fentanyl through the buccal mucosa, decreasing the amount absorbed gastrointestinally and therefore decreasing CYP3A4mediated metabolism. This enhanced buccal absorption may improve bioavailability and the drug-interaction profile. 4 The differences in PK parameters observed in this study are consistent with the hypothesis that the effervescence reaction facilitates a greater buccal absorption of fentanyl with FEBT compared with the noneffervescent OTFC formulation. Thus, although a smaller dose of fentanyl was administered with FEBT (1080 lag) than with OTFC (1600 lag) in this study, a comparable amount reached the systemic circulation. Because successful administration of an opioid often requires titration to an effective dose, it is important that FEBT provide predictable increases in drug concentration with each increase in dose. A linear, doseMay2006
proportional PK profile has been found with FEBT across a dose range of 100 to 800 lag. (See the companion article, "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," by Darwish et al, in this issue.) This exploratory assessment of the single-dose PK profile and tolerability of FEBT suggests that it is dose proportional across the range of 270 to 1300 lag based on total systemic exposure of fentanyl (AUC0~). The less-than-proportional increase in C m ~ ~ found at FEBT doses >810 lag might be a function of saturation at the site of FEBT absorption, with the buccal mucosa acting as a "depot" for absorption of fentanyl following administration of FEBT, resulting in blunted peak profiles following administration of the higher doses (1080 and 1300 lag) of FEBT compared with administration of FEBT 810 lag. Therefore, the less-than-proportional increases in Cmax were offset by more sustained serum concentrations around the peak, which resulted in proportional increases in overall systemic exposure (AUC0~). All studies employing an open-label design in healthy volunteers are subject to limitations. Although the study was appropriately designed and adequately powered to assess the relative bioavailability of FEBT versus OTFC, the parallel-group design used to characterize 3 of the 4 dosing regimens resulted in inadequate power to assess dose proportionality over the full dose range. Furthermore, the PK profile of fentanyl derived from healthy subjects might not be representative of the PK profile in patients with medical conditions, particularly those associated with hepatic impairment, or in subjects receiving concomitant medications likely to alter the metabolic pathway of the drug. The implications of higher Cmax values with FEBT compared with that of OTFC could not be assessed in this study because the subjects were administered naltrexone. These confounding factors are typically assessed in studies designed to address these needs. An additional limitation of this study was that the concentration of the fentanyl metabolite norfentanyl was not measured. Thus, a direct demonstration of the decreased CYP3A4-mediated metabolism of fentanyl expected with increased absorption of fentanyl was not possible. CONCLUSIONS
In this PK study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up 723
Clinical Therapeudcs
to FEBT 1300 pg, whereas doses above 810 pg showed a less-than-dose-proportional increase in Cm=. The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (Cn~ x and AUCc~T~, ) and significantly faster (Tm=) with FEBT compared with OTFC. ACKNOWLEDGMENTS This article was sponsored by Cephalon, Inc., Frazer, Pennsylvania. We thank James Kasicki, MD, and the staff at MDS Pharma Services for their help in the conduct of the study and Elizabeth A. Young, PhD, and Anita P. Kuan, PhD (Envision Pharma, Inc., Southport, Connecticut), for their assistance in preparing the manuscript. REFERENCES
1. Stanley TH. Fentanyh j Pain Symptom Manage. 2005;29 (Suppl 5):$67 $71. 2. Bennett D, Burton AW, Fishman S, et ah Consensus panel recommendations for the assessment and managementof breakthrough pain: Part 2 management. PharmTher. 2005; 30:354 361. 3. Pather SI, Siebert JM, Hontz J, et ah Enhanced buccal delivery o f fentanyl using the OraVescent drug delivery system. Drug Deliv Tech. 2001 ;1:54 5Z 4. Dun'ee S, MessinaJ, Khankari RK. Fentanyl effervescent buccal tablets: Enhanced buccal absorption. Amy Drug Deliv. 2006;4:1 5. 5. Eichman JD, Robinson JR. Mechanistic studies on effervescent induced permeability enhancement. Pkarm Res. 1998;15:925 930.
6. Eichman JD, Yassin AE DB, Robinson JR. The influence of in vivo carbonation on GI physiological processes and drug permeability. Eurj Pharm Biopharm. 1997;44:33 38. 7. Fine PG, Marcus M, De BoerAJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991; 45:149 153. 8. Darwish M, Tempero K, Kirby M, Thompson J. Pharmacokinetics and dose proportionality o f fentanyl effervescent buccal tablets in healthy volunteers. Clin Pkarmacokinet. 2005;44:1279 1286. 9. European Agency for the Evaluation of Medicinal Products, International Conference on Harmonisation World Health Organization. Guideline for Good Clinical Practice [EMEAWeb site]. ICH Topic E6. Geneva, Switzerland: WHO; 2002. Avail able at: http://www.emea.eu.int. Accessed April 13, 2006. 10. 1983 Metropolitan height and weight tables. Stat Bull Metrop Life,Found. 1983;64:3 9. 11. Actiq (oral transmucosal fentanyl citrate 400 pg) [prod uct information[. Frazer, Pa: Cephalon, Inc; 2004. 12. US Dept of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Available at: http://www.fda. gov/cder/guidance/3616fnhpdf. Accessed April 26, 2005. 13. Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment o f dose pro portionality. Pharm Res. 2000;17:1278 1283. 14. US Food and Drug Administration (FDA). Catalog o f FDA Approved Drug Products: Actiq (NDA) #020747 Drug Details. Available at: http://www.accessdata.fda.gov/ scripts/cdet/drugsalfda/index.cfm?fuseaction Search.Drug Details. Accessed February 9, 2006.
Address correspondence to: Mona Darwish, PhD, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355. E-maih mdarwish(c~cephalon.com 724
Volume 28 Number 5
Relative Bioavailability of the 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, Three-Period Study in Healthy Adult Volunteers Mona
Darwish,
Jeffrey Thompson,
PhD1; Kenneth Tempero,
M D , P h D 2 ; M a r y Kirby, MS1; a n d
MS, MBA 2
l Cepkalon, Inc., Frazer, Pennsylvania; and 2CIMA Laboratories, Eden Prairie, Minnesota ABSTRACT
Background:The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain. Objectives: The primary objective of this study was to compare the relative bioavailability of FEBT 1080 lag with that of oral transmucosal fentanyl citrate (OTFC ®) 1600 lag, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1300 lag in healthy adult volunteers. Methods: This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1080 lag followed by single-dose OTFC 1600 lag, or vice versa; in period 3 (doseproportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1300 lag. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 lag, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For toleraMay 2006
bility analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed. Results:A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC0~ ) was statistically similar between FEBT 1080 lag and OTFC 1600 lag (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng. h/mL). However, the mean (SD) Cm= with FEBT 1080 lag was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1600 lag (P = NS), and the Tn~x of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC 0 Tma~; ie, AUC from time 0 to 1 hour [the median T of the reference dose of FEBT [810 lag]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] n g . h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC0~ and A U C 0 ~ , over the range of FEBT 270 to 1300 lag. Itlis workwas previously published in abstract form: Darwish M, Messina J, Tempero K. Relative bioavailability and dose pro portionality o f a novel effervescent form o f fentanyl in healthy volunteers. Anesthesiolo~. 2005;103:A790. Available at: http:// www'asaabstracts'c° m/stran ds/asaabst racts/abst ract'h t m ; jsessionid 0E021F123BAA6313802B30Eg044FB145?year 2005 &index 6&absnum 1066.
AcceptedforpublicationMarch29, 2006. doi:10.1016/j.clinthera.2006.05.016 0149 2918/06/$19.00 Printed in the USA.Reproduction in wholeor part is not permitted. Copyright© 2006 ExcerptaMedica,Inc. 71 S
Clinical Therapeutics Increases in Cn~x were less than dose proportional at FEBT doses >810 lag. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects], nausea (1 [2%]], upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT. Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC. Conclusions: In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1300 lag, whereas doses above 810 lag showed a less-than-doseproportional increase in Cn~x. The results suggest that fentanyl enters the systemic circulation to a significantly greater extent ( C ~ and AUC0~max,) and significantly more rapidly ( T ) with FEBT compared with OTFC. (Clin Ther. 2006;28:715-724) Copyright © 2006 Excerpta Medica, Inc. Key words: fentanyl, fentanyl effervescent buccal tablet, oral transmucosal fentanyl citrate, pharmacokinetics, effervescence.
INTRODUCTION Fentanyl is a well-studied, highly lipophilic, p-opioidreceptor agonist used as an anesthetic and analgesic. 1,2 Fentanyl effervescent buccal tablet (FEBT), a formulation designed for rapid absorption through the buccal mucosa,3,4 is being investigated for the management of breakthrough pain. At the site of administration, FEBT produces an effervescence reaction that liberates carbon dioxide, which becomes carbonic acid in solution. The reaction causes a decrease in pH, followed by the release of sodium carbonate, which increases pH. This decrease and increase in pH are hypothesized to optimize dissolution and membrane permeation, respectively, of fentanyl, facilitating rapid absorption through the buccal mucosa.3 s This rapid absorption might decrease the time to onset of analgesia suitable for the management of breakthrough pain. 716
The primary objective of this study was to compare the relative bioavailabilities of single-dose FEBT 1080 lag and oral transmucosal fentanyl citrate (OTFC ®) 1600 lag in healthy volunteers. OTFC was chosen as the comparator for the pharmacokinetic (PK) profile of FEBT because it uses a transmucosal delivery system. 7 A secondary objective was to assess the dose proportionality of FEBT at doses up to 1300 lag,which includes doses higher than those previously studied (_<800 lag).s (See the companion article in this issue, "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," by Darwish et al.) SUBJECTS A N D METHODS This randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. The study protocol was approved by the institutional review board (IRB) at MDS and carried out in full accordance with the Good Clinical Practice: Consolidated Guideline. 9 Inclusion and Exclusion Criteria Eligible volunteers were men and women aged 19 to 55 years who were non-opioid tolerant, with normal findings on medical history, physical examination (height, weight, frame size [normal weight was defined as -+15% of the ideal weight for height and estimated frame size1°], vital signs, and electrocardiography [ECG]), and clinical laboratory analysis (hematology, serum chemistry, urinalysis, HIV antibody screen, hepatitis B surface antigen screen, hepatitis C antibody screen, and serum pregnancy [women]) within 21 days before study enrollment, and reported to have been nicotine- and tobacco-free for 26 months before enrollment. Volunteers with positive results on screening for cannabinoids and/or opioids were exclude& All volunteers read and signed an IRB-approved informed-consent form before study procedures were performed and were financially compensated for their participation. Study Design Bioavailability was assessed in the first 2 administration periods of the study. Eligible subjects were randomly assigned, using a computer-generated randomization scheme, to 1 of 2 administration sequences: single-dose FEBT 1080 lag followed by single-dose Volume 28 Number S
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OTFC 1600 pg, or vice versa. The third period of the study employed a parallel-group design in which subjects were re-randomized to receive a single dose of FEBT 270, 810, or 1300 pg. Each study period was separated by a 7-day washout period (Figure 1). Over-the-counter medications were prohibited for 7 days before and during the study. Prescription medications were not allowed for 14 days before and during the study (with the exception of hormonal contraceptives for women). Subjects were asked not to consume any alcohol-, broccoli-, citrus-, caffeine-, or xanthine-containing foods or beverages for 48 hours before and during each study period. Strenuous physical activity was not allowed during the study. Study D r u g Administration and Pharmacokinetic Assessment Subjects arrived at MDS on the day before study drug administration. Standardized meals were provided, and subjects fasted for - 1 0 hours before study
drug administration on the following morning. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. If after 10 minutes a portion of the tablet remained, subjects were instructed to gently massage the cheek in the location of the tablet until it completely dissolved. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes (in accordance with the package insert11). If the OTFC lozenge did not dissolve completely after 15 minutes, it was allowed to continue to dissolve and the time to complete dissolution was recorded. Subjects were asked to remain seated for 4 hours after fentanyl administration, during which water intake was prohibited. Subjects were observed for 36 hours after fentanyl administration. Because subjects were not opioid tolerant, naltrexone hydrochloride, an opioid antagonist, was admin-
Healthy subjects screened <21 Days Subjects meeting inclusion criteria and undergoing randomization (N 42)
FEBT 1080 IJg (n 21) v OTFC 1600 ,ug (n 21)
OTFC® 1600 IJg (n 21)
7 Day washout
v FEBT 1080 ,ug (n 19)
Period 1
Period 2
Second randomization
(n 39) 7 Day washout
FEBT270 #g (n 14)
FEBT810 #g (n 13)
FEBT1300 #g (n 12)
Period 3
Figure 1. Study design. FEBT = fentanyl effervescent buccal tablet; OTFC = oral transmucosal fentanyl citrate.
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Clinical Therapeudcs istered to block the opioid receptor-mediated effects of fentanyl. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 lag, who were not given naltrexone at 12 hours because of the low dose they were receiving. Venous blood samples (7 mL) were collected at the following times in subjects receiving FEBT 810, 1080, or 1300 lag, or OTFC 1600 lag: before (time 0; baseline) and 10, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36 hours after study drug administration. In subjects receiving FEBT 270 lag, venous blood samples (7 mL) were collected before (time 0; baseline) and 10, 20, 30, and 45 minutes and 1, 2, 4, 6, 8, 9, 10, 11, 12, 14, 16, 20, and 24 hours after study drug administration. Blood samples were collected by venipuncture into 7-mL tubes with no additive. Samples were allowed to clot at room temperature, centrifuged (2400 rpm at 4°C for 15 minutes), and stored at -20°C until analyzed. Serum concentrations of fentanyl were determined by MDS Pharma Services using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS). Internal standard, D-5fentanyl, was added and the analyte was extracted from human serum using liquid-liquid extraction under basic conditions. The linear range for the assay was 50.0 to 5000.0 pg/mL, with a limit of quantitation of 50.0 pg/mL. The method has reported selectivity against naltrexone up to concentrations of 10 ng/mL. Stability of fentanyl has been demonstrated in serum stored at -20°C for 32 weeks and stored at room temperature for 24 hours. The assay was considered accurate at CV _<7.89%. No interference in the assay was produced either by endogenous species in serum or by naltrexone. Concentrations less than the quantifiable limit of 50.0 pg/mL were recorded as 0. Tole rability Analysis For tolerability analysis, vital signs (sitting blood pressure, heart and respiratory rates) were measured each morning before study drug administration (time 0; baseline), at 15-minute intervals for 4 hours after administration, and at 5, 6, 8, 10, 24, and 36 hours after administration. Continuous pulse oximetry was conducted for the first 8 hours after dosing. At the screening visit and the conclusion of the study, a 12-lead ECG; clinical laboratory analysis (hematology, serum chemistry, and urinalysis); and physical examination, 718
including vital-sign measurements, were performed. Clinical laboratory tests were performed at MDS Pharma Services Clinical Laboratory, an accredited laboratory facility. Quality control material was run with each batch of samples (for serum chemistry tests), once per shift (for hematology tests), or every 24 hours (for urinalysis). Automated equipment was used to measure the vital signs of each subject. A blood pressure machine with oxygen saturation measurement capabilities (Critikon, GE Healthcare, Giles, United Kingdom) was attached to each subject's finger and connected to the automated equipment. Oxygen saturation was continuously monitored for 8 hours after study drug administration. Limits set for monitoring were within the range of 90% to 100% oxygen saturation. Subjects were instructed to inform the physician and/or nurses of any adverse events (AEs) that occurred during the study. To assess the effects of oral transmucosal delivery, each subject's oral mucosa was inspected for sores in the area of drug application at the beginning of each study period. Four hours after administration, subjects were asked how the area of drug application felt. The area was also inspected by a nurse, w h o recorded the subjects' answers and the results of the assessments.
Statistical Analyses The study was designed to enroll 42 volunteers for - 9 2 % power to assess relative bioavailability of FEBT and OTFC using a bioequivalence approach. 12,13 The sample size was not powered to assess dose proportionality; therefore, all dose-proportionality analyses in this study are exploratory. The dose-proportionality portion of the study was partly conducted in parallel. All of the subjects received FEBT 1080 lag in the relative bioavailability portion of the study (compared with OTFC 1600 lag). Subsequently, subjects were randomized to 1 of 3 groups and each group received one of the remaining FEBT doses (270, 810, or 1300 lag) in a parallel-group design. PK data from all 4 FEBT groups (270, 810, 1080, and 1300 lag) were used in the assessment of dose proportionality. The PK parameters--Cn~x, Tn~x, terminal elimination rate constant (Kel), elimination half-life (tl/2) , AUC04 , AUC0~ , AUC04/AUC0~ ratio, and AUC from time 0 to time of m a x i m u m concentration of fentanyl (AUC 0 T ~ x ) - - w e r e computed from the fentanyl concentration- time data for each dose. Early systemic exposure (AUCTmaf; ie, AUC from time 0 to 1 hour [the Volume 28 Number S
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median T of the reference dose, FEBT 810 lag]) was calculated post hoc, using noncompartmental methods. The relative bioavailability of FEBT 1080 lag versus OTFC 1600 lag was assessed using a bioequivalence approach. A parametric (normal theory) general linear model was applied to the logarithm (ln)-transformed C ~ , AUC04, and AUC0~ values. The multivariate analysis of variance (ANOVA) model included the following factors: sequence, subject within sequence, period, and drug administration. The two 1-sided hypotheses were tested at the 5% level for C ~ o AUCc~t, and AUC0~ by constructing 90% CIs for the mean ratios of FEBT 1080 lag to OTFC 1600 lag. Bioequivalence was concluded if the calculated CI fell within 80% to 125% of the ratio. 12 Differences in T ~ for the administration of FEBT 1080 lag and OTFC 1600 lag were assessed using the Wilcoxon signed rank test (c~ = 0.05). To explore the dose proportionality of FEBT, a general linear model was applied to dose-normalized Cm= and AUC parameters. The dose-by-group interaction was not significant for 2 of the 3 parameters ( C ~ and AUCc~t) , and the model was reduced to a 1-way ANOVA with the factor of dose. When an overall dose effect was found, pairwise comparisons were performed using the 1080-1Jg dose of FEBT as the reference because all subjects had received this dose. An additional analysis of dose proportionality from 270 to 1300 lag was performed using a 90% CI on the slope, [3, of the regression line: ln(PK) = c~ + [3In(dose) + e where the random error term e was modeled to account for both intrasubject and intersubject variation. A mixedeffects model was implemented to provide a 90% CI for the fixed effect of [3. If the CI fell completely within the limits (0.8580-1.1420), dose proportionality was concluded. 13 SAS version 6 (SAS Institute Inc., Cary, North Carolina) was used in the statistical analysis. RESULTS Study Population A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Two subjects withdrew after receiving 1 dose of OTFC (1600 ~g) in period 1 (1 for personal reasons, 1 for receiving an antibiotic); data from these subjects were excluded from the relative-bioavailability and doseMay2006
proportionality analyses. A third subject withdrew for personal reasons before beginning period 3; the data from this subject were included in the relative bioavailability analyses but not the dose-proportionality analysis. Post hoc analyses confirm that exclusion of the first 2 subjects mentioned did not affect the results of the relative-bioavailability analysis, and that the exclusion of data from all 3 subjects did not affect the results of the dose-proportionality analysis. A demographic summary of subjects is provided in Table I. Pharmacokinetic Properties AUCs for FEBT 270-, 810-, 1080-, and 1300-~g doses are shown in Figure 2, and the PK parameters of FEBT doses are shown in Table II. Mean serum fentanyl concentrations exhibited a bi- or triexponential decline from Cn~x, depending on how well the terminal portion of the curve was characterized. The range of tl/2 values was 6.6 to 13.2 hours (Table II). Tn~x values were comparable among FEBT 270-, 810-, and 1080-~g doses (median, 0.9-1.2 hours) and were longer after administration of the 1300-~g dose (median, 1.5 hours).
Table I. Demographic and baseline clinical characteristics of the study subjects (N = 42). Characteristic
Value
Age, y Mean (SD) Range
27 (11) 19 55
Sex, no. Female Male Race, no. White Asian European/Middle Eastern Hispanic Native American
25 17 33
4 2 2 1
Weight., mean (SD), kg
68.4 (8.7)
BMI, kg/m 2 Mean (SD) Range
23.1 (2.4) 18.8 28.3
BMI
bodymass index.
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Clinical T h e r a p e u d c s
FEBT270pg(n . ~ FEBT810pg(n FEBT1080pg (n FEBT1300pg(n
14) 13) 40) 12)
3.0
2.5 2.0
~" E
2.5
1.5
v ~
1.0 2.0
0.5
c
0
= o U
1.5
~
1.o
0
2
4
6
8
28
30
10
12
£ E
o;~ 0
2
4
6
8
10
12
14
16
18
20
22
24
26
32
34
36
Time Afrer Study Drug Administration (h) Figure 2. Mean (SEM) serum drug concentrations after administration of fentanyl effervescent buccal tablet (FEBT) 270, 810, 1080, and 1300 IJg. Inset is an expanded view (with no error bars) o f the first 12 hours after administration of FEBT.
Table II. Dose-proportionality evaluation: Pharmacokinetic (PK) properties offentanyl effervescent buccal tablet as measured in serum. Values are mean ( S D ) .
PK Proper~ C .... ng/mL Tm~ , h AUC0 t, ng" h/mL AUC0~ , ng" h/mL AUC 0 r/AUC 0 ~ ratio AUC0~ .... ng" h/mL tl/2, h Dose normalized values Cma~dose , pg" pg/mL* AUC 0 r/dose, pg" h/mL/pg AUC0~/dose , pg" h/mL/pg
270ug (n 14)
810ug (n 13)
1080 ug (n 40)
1300 ug (n 12)
0.8 (0.3) 1.2 (0.6) 4.3(1.6) 4.2 (1.7) 0.87 (0.04) 1.1 (0.4) 6.6(3.2)
2.6 (0.8) 0.9 (0.4) 15.3(4.3) 16.8 (4.4) 0.91 (0.04) 3.7 (1.0) 11.7(4.7)
2.7 (0.9) 1.1 (0.6) 16.5(5.5) 17.7 (5.4) 0.92 (0.0S) 3.8 (1.3) 11.7(5.0)
2.8 (0.9) 1.5 (1.0) 18.9(6.5) 21.0 (7.3) 0.91 (0.07) 4.0 (1.3) 13.2(7.7)
3.0 (1.2) 16.1 (5.9) 15.6 (6.5)
3.3 (1.0) 18.9 (5.3) 21.0 (5.5)
2.5 (0.8) 15.5 (5.0) 17.0 (5.0)
2.1 (0.7) 14.6 (5.0) 16.2 (5.7)
AUC0 Tmax= AUC from time 0 to time of maximum concentration of fentanyl. *P = 0.013 (analysis of variance of logarithm transformed dose normalized Crrax values).
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M. Darwish et all.
Relative Bioavailability The PK parameters obtained with FEBT 1080 pg and OTFC 1600 pg are shown in Table IlL Total systemic exposure (as measured using AUC0~ ) was statistically similar between these 2 study drugs (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng. h/mL). The estimated mean FEBT/OTFC ratios for AUC04 and AUC0~ were 1.014 and 1.011, respectively. The CI values for these ratios fell within the pre-established criterion for bioequivalence. Eased on the C ratio of 1.23 (90% CI, 1.118-1.362) for FEBT/OTFC, the 2 formulations did not meet the criterion for bioequivalence at the administered dose strengths because the upper 90% confidence limit of the C ~ ratio exceeded the upper limit for bioequivalence. Administration of FEBT also yielded higher early systemic exposure of fentanyl compared with OTFC administration, as measured using median T (1.0 vs 2.0 hours; P < 0.001) and mean (SD) A U C 0 ~ x, (1.5 [0.5] vs 0.8 [0.4] ng. h/mL; P < 0.001) (Figure 3 and Table III).
Analysis of the slopes of ln(Cn~x), In(AUC04), In(AUC0~), and In(AUCc~Tmag) versus In(dose) is shown in Table IV. This analysis found that fentanyl exposure, as determined by C ~ , increased in a less-thandose-proportional manner. The less-than-proportional increases in C ~ were offset by more sustained serum concentrations around the peak. This resulted in proportional increases in overall systemic exposure (as determined by AUC0~ ) that were linear over the range of 270 to 1300 pg (90% CIs for this parameter were completely contained within the critical range required for dose proportionality [0.8580-1.1420]). As noted above, T ~ x was comparable among FEET 270-, 810-, and 1080-pg doses and was slightly longer with FEET 1300 pg. Comparable tl/2 values were seen with the FEET 810-, 1080-, and 1300-pg doses. However, the tl/2 of the 270-pg dose was lower by -50% compared with the other 3 doses because the serum fentanyl concentration was less than the limit of detection at the terminal portion of the curve in 10 (71%) of 14 subjects who received this dose.
Dose Proportionality Dose-normalized total fentanyl exposures were comparable across FEET 270-, 810-, 1080-, and 1300-pg doses (AUC0 t/dose , range, 14.6-18.9 pg . h/mL/pg; AUC0 /dose , range, 15.6-21.0 pg. h/mL/pg; Table II). An initial ANOVA of the (In)dose-normalized C ~ values to assess dose proportionality found an overall dose effect (P = 0.013) (Table II). Therefore, pairwise comparisons of dose-normalized Cn~ were analyzed using the 1080-pg FEET dose as a reference; a difference was found only between FEET 810- and 1080-pg doses (P = 0.018).
Tolerability Definitive attribution of AEs to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone (to block opioid receptor-mediated effects). With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, vomiting, lightheadedness), and most (89.6%) were mild. No se-
Table III. Relative bioavailability assessment: pharmacokinetic properties o f fentanyl effervescent buccal tablet (FEB]-) and oral transmucosal fentanyl citrate (OTFC ~) as measured in serum (n = 40). Values are mean (SD) unless otherwise specified. Cmax~ ng/mL
ng ~ h/mL
AUCo ~, ng ~ h/mL
FEBT 1080 IJg
2.7(0.9)
16.0(5.5)
18.0(5.4)
1.5(0.5)*
1.0(0.3 2.0)*
OTFC 1600 Hg
2.2(0.7)
17.0(6.5)
18.0(7.1)
0.8(0.4)
2.0(0.8 4.0)
1.234 (1.118 1.362)
1.014 (0.944 1.089)
1.011 (0.936 1.092)
FEBT:OTFC ratio, ....... (90% CI)f
AUCo t,
AUCo~mJ, ng ~ h/mL
Tmax, Median (range), h
AUC0~ma/ AUC from time 0 to 1 hour (the median Tma×of the reference dose of FEBT [810 ~lg]). *P < 0.001 versus OTFC. fFEBT:OTFC ratio exponential (test reference) for logarithm transformed parameters.
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Clinical Therapeudcs
30
I
FEBT1080 pg(n = 40) OTFC 1600 pg(n = 40) 2.5
2.0
2 E
2.5
1.5 1.0
2.0
0.5
~: c
;
° 0
1.5
;
110
112
1.0
E o.s
0 -~T 0
2
q 4
T 6
q 8
T 10
F 12
T 14
F 16
T 18
F 20
q 22
g 24
q 26
T 28
q 30
T 32
q ~ 34 36
T i m e A f t e r S t u d y D r u g A d m i n i s t r a t i o n (h)
Figure 3. Mean (SEM) serum drug concentrations after administration of fentanyl effervescent buccal tablet (FEBT) 1080 pg or oral transmucosal fentanyl citrate (OTFC ~) 1600 pg. Inset is an expanded view (with no error bars) of the first 12 hours after administration of FEBT or OTFC.
Table IV. Dose-proportionality assessment using the fixed effect for slope (n = 40). Parameter
Slope (90% CI*)
In(Crrax)
0.8673 (0.7991 0.9356)
In(AUC0t)
0.9634 (0.9061 1.0206)
In(AUCo~ )
0.9376 (0.8697 1.0054)
In(AUC0~rcat )
0.9400 (0.8518 1.0283)
In logarithm transformed; AUC0~ma~ AUC fiom time 0 to 1 hour (the median Trr~xof the reference dose offentanyl effervescent buccal tablet [810 I]g]). *90% CI within the critical range of 0.8580 to 1.1420 is consistent with dose proportionality.
rious AEs were observed. One case each of mild oral irritation and redness were reported after the administration of FEBT. Both occurrences resolved within 4.5 hours. N o oral irritation or redness was reported after the administration of OTFC. 722
DISCUSSION A lower dose (1080 lag) of FEBT produced a total systemic fentanyl exposure (AUC0~) comparable with a higher dose (1600 lag) of O T F C in this PK comparison in these healthy volunteers. Early systemic fentanyl exposure (as measured by AUC0~n~ x, and C x) was proportionally greater (88% and 2 3 % , respectively) and occurred significantly earlier (as measured by T ~ x ) with FEBT compared with O T F C (P < 0.001). Both drugs were well tolerated, although attribution of AEs to either fentanyl formulation was confounded by the concomitant administration of naltrexone. The exploratory assessment of close proportionality suggests that FEBT was close proportional across the range of 270 to 1300 lag based on total systemic exposure of fentanyl (AUC0~), but increases in C ~ with FEBT at doses higher than 810 lag were less than proportional. At the lowest dose of FEBT (270 lag), the serum concentration was less than the lower limit of detection at the terminal portion of the curve in most (71%) subjects, which prohibited the accurate Volume 28 Number S
M. Darwish et al.
characterization of the terminal portion of the curve at this dose and might have affected the calculation of tl/2 with this dose. OTFC is the first and only medication specifically approved in the United States for the treatment of cancer-related breakthrough pain in opioid-tolerant patients. 14 The effervescence delivery system of FEBT alters the PK profile of fentanyl in a way that might offer advantages over the noneffervescent OTFC formulation. Comparable total systemic fentanyl exposure (AUC0~) of FEBT 1080 lag and OTFC 1600 lag (mean FEBT:OTFC ratio, 1.011) suggests that a dose of FEBT would result in greater systemic exposure to fentanyl compared with a lag-equivalent dose of OTFC. The AUC0 Tn~x"was significantly greater with FEBT 1080 lag compared with OTFC 1600 lag (P < 0.001), reflecting the rapid entry of FEBT into the systemic circulation. Whether these PK differences would result in clinically meaningful differences between FEBT and OTFC needs confirmation in controlled clinical studies of patients with breakthrough pain. Transmucosal absorption allows fentanyl to bypass first-pass cytochrome P450 (CYP) 3A4-mediated gastrointestinal and/or hepatic metabolism. Thus, increasing the proportion of the dose undergoing transmucosal absorption allows more fentanyl to enter the systemic circulation compared with the gastrointestinal absorption of an equivalent amount of swallowed fentanyl. 3,4,n Seventy-five percent of the fentanyl from OTFC is swallowed and absorbed gastrointestinally, and is thus subject to CYP3A4-mediated first-pass metabolism in both intestinal and hepatic microsomes. 4 The formulation of FEBT may enhance absorption of fentanyl through the buccal mucosa, decreasing the amount absorbed gastrointestinally and therefore decreasing CYP3A4mediated metabolism. This enhanced buccal absorption may improve bioavailability and the drug-interaction profile. 4 The differences in PK parameters observed in this study are consistent with the hypothesis that the effervescence reaction facilitates a greater buccal absorption of fentanyl with FEBT compared with the noneffervescent OTFC formulation. Thus, although a smaller dose of fentanyl was administered with FEBT (1080 lag) than with OTFC (1600 lag) in this study, a comparable amount reached the systemic circulation. Because successful administration of an opioid often requires titration to an effective dose, it is important that FEBT provide predictable increases in drug concentration with each increase in dose. A linear, doseMay2006
proportional PK profile has been found with FEBT across a dose range of 100 to 800 lag. (See the companion article, "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," by Darwish et al, in this issue.) This exploratory assessment of the single-dose PK profile and tolerability of FEBT suggests that it is dose proportional across the range of 270 to 1300 lag based on total systemic exposure of fentanyl (AUC0~). The less-than-proportional increase in C m ~ ~ found at FEBT doses >810 lag might be a function of saturation at the site of FEBT absorption, with the buccal mucosa acting as a "depot" for absorption of fentanyl following administration of FEBT, resulting in blunted peak profiles following administration of the higher doses (1080 and 1300 lag) of FEBT compared with administration of FEBT 810 lag. Therefore, the less-than-proportional increases in Cmax were offset by more sustained serum concentrations around the peak, which resulted in proportional increases in overall systemic exposure (AUC0~). All studies employing an open-label design in healthy volunteers are subject to limitations. Although the study was appropriately designed and adequately powered to assess the relative bioavailability of FEBT versus OTFC, the parallel-group design used to characterize 3 of the 4 dosing regimens resulted in inadequate power to assess dose proportionality over the full dose range. Furthermore, the PK profile of fentanyl derived from healthy subjects might not be representative of the PK profile in patients with medical conditions, particularly those associated with hepatic impairment, or in subjects receiving concomitant medications likely to alter the metabolic pathway of the drug. The implications of higher Cmax values with FEBT compared with that of OTFC could not be assessed in this study because the subjects were administered naltrexone. These confounding factors are typically assessed in studies designed to address these needs. An additional limitation of this study was that the concentration of the fentanyl metabolite norfentanyl was not measured. Thus, a direct demonstration of the decreased CYP3A4-mediated metabolism of fentanyl expected with increased absorption of fentanyl was not possible. CONCLUSIONS
In this PK study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up 723
Clinical Therapeudcs
to FEBT 1300 pg, whereas doses above 810 pg showed a less-than-dose-proportional increase in Cm=. The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (Cn~ x and AUCc~T~, ) and significantly faster (Tm=) with FEBT compared with OTFC. ACKNOWLEDGMENTS This article was sponsored by Cephalon, Inc., Frazer, Pennsylvania. We thank James Kasicki, MD, and the staff at MDS Pharma Services for their help in the conduct of the study and Elizabeth A. Young, PhD, and Anita P. Kuan, PhD (Envision Pharma, Inc., Southport, Connecticut), for their assistance in preparing the manuscript. REFERENCES
1. Stanley TH. Fentanyh j Pain Symptom Manage. 2005;29 (Suppl 5):$67 $71. 2. Bennett D, Burton AW, Fishman S, et ah Consensus panel recommendations for the assessment and managementof breakthrough pain: Part 2 management. PharmTher. 2005; 30:354 361. 3. Pather SI, Siebert JM, Hontz J, et ah Enhanced buccal delivery o f fentanyl using the OraVescent drug delivery system. Drug Deliv Tech. 2001 ;1:54 5Z 4. Dun'ee S, MessinaJ, Khankari RK. Fentanyl effervescent buccal tablets: Enhanced buccal absorption. Amy Drug Deliv. 2006;4:1 5. 5. Eichman JD, Robinson JR. Mechanistic studies on effervescent induced permeability enhancement. Pkarm Res. 1998;15:925 930.
6. Eichman JD, Yassin AE DB, Robinson JR. The influence of in vivo carbonation on GI physiological processes and drug permeability. Eurj Pharm Biopharm. 1997;44:33 38. 7. Fine PG, Marcus M, De BoerAJ, Van der Oord B. An open label study of oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough cancer pain. Pain. 1991; 45:149 153. 8. Darwish M, Tempero K, Kirby M, Thompson J. Pharmacokinetics and dose proportionality o f fentanyl effervescent buccal tablets in healthy volunteers. Clin Pkarmacokinet. 2005;44:1279 1286. 9. European Agency for the Evaluation of Medicinal Products, International Conference on Harmonisation World Health Organization. Guideline for Good Clinical Practice [EMEAWeb site]. ICH Topic E6. Geneva, Switzerland: WHO; 2002. Avail able at: http://www.emea.eu.int. Accessed April 13, 2006. 10. 1983 Metropolitan height and weight tables. Stat Bull Metrop Life,Found. 1983;64:3 9. 11. Actiq (oral transmucosal fentanyl citrate 400 pg) [prod uct information[. Frazer, Pa: Cephalon, Inc; 2004. 12. US Dept of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Available at: http://www.fda. gov/cder/guidance/3616fnhpdf. Accessed April 26, 2005. 13. Smith BP, Vandenhende FR, DeSante KA, et al. Confidence interval criteria for assessment o f dose pro portionality. Pharm Res. 2000;17:1278 1283. 14. US Food and Drug Administration (FDA). Catalog o f FDA Approved Drug Products: Actiq (NDA) #020747 Drug Details. Available at: http://www.accessdata.fda.gov/ scripts/cdet/drugsalfda/index.cfm?fuseaction Search.Drug Details. Accessed February 9, 2006.
Address correspondence to: Mona Darwish, PhD, Cephalon, Inc., 41 Moores Road, Frazer, PA 19355. E-maih mdarwish(c~cephalon.com 724
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