Vol. 26 No. 2 August 2003 Journal of Pain and Symptom Management 743

Original Article

A Pharmacokinetic Study to Compare TwoSimultaneous 400 µg Doses with a Single800 µg Dose of Oral TransmucosalFentanyl CitrateMaureen Lee, PharmD, Steven E. Kern, PhD, James C. Kisicki, MD,and Talmage D. Egan, MDCollege of Pharmacy (M.L.), Department of Pharmaceutics (S.E.K.), and Department ofAnesthesiology (S.E.K., T.D.E.), University of Utah, Salt Lake City, Utah; and MDS HarrisLaboratories (J.C.K.), Lincoln, Nebraska, USA

AbstractIt is unknown whether two smaller doses of oral transmucosal fentanyl citrate (OTFC)administered simultaneously are pharmacokinetically equivalent to an identical doseadministered as a single unit. This issue has important practical implications whenpatients are attempting to identify the appropriate dosage of OTFC to control their pain.This open-label, randomized, crossover design study compared the pharmacokinetics of twosimultaneously consumed 400 mg OTFC doses with one 800 mg OTFC dose in 12 healthyvolunteers. The two treatments were pharmacokinetically equivalent. The maximumconcentration produced for each dosage group (Cmax) was 1.09 ng/ml for two 400 mgdose and 1.10 ng/ml for one 800 mg dose. Area under the curve (AUC) was 8.2 ng/ml·hr(SE � 1.1) and 7.2 ng/ml·hr (SE � 1.0). There were no significant differences betweenthe treatment groups in either the time to peak concentration (Tmax) or the mean residencetime (MRT). The results demonstrate the bioequivalence of two 400 mg with one 800 mgOTFC units. J Pain Symptom Manage 2003;26:743–747. � 2003 U.S. Cancer PainRelief Committee. Published by Elsevier Inc. All rights reserved.

Key WordsFentanyl, Actiq, OTFC, pharmacokinetics, bioequivalence, opioids

IntroductionBreakthrough pain is a transitory exacerba-

tion of pain that occurs in addition to back-

Address reprint requests to: Steven E. Kern, PhD, Depart-ment of Pharmaceutics, University of Utah, 421Wakara Way, Suite 318, Salt Lake City, UT 84108,USA.Accepted for publication: December 12, 2002.

� 2003 U.S. Cancer Pain Relief CommitteePublished by Elsevier Inc. All rights reserved.

ground or persistent pain in patients withchronic pain conditions.1 Oral transmucosalfentanyl citrate (OTFC) has been shown to bean effective drug delivery method for break-through pain relief.1,2 Fentanyl is absorbedfrom the OTFC unit into the circulationthrough the oral mucosa. This direct entry offentanyl into the circulation avoids first passmetabolism, allowing the patient to obtain ef-fective opioid levels more rapidly than oral ad-ministration.3 The noninvasive nature of OTFC

0885-3924/03/$–see front matterdoi:10.1016/S0885-3924(03)00241-0

744 Vol. 26 No. 2 August 2003Lee et al.

gives the patient a convenient method to self-titrate analgesia in a relatively short periodof time for the management of breakthroughpain.

OTFC (Actiq, Cephalon Inc, West Chester,PA) is approved for the management of break-through cancer pain in patients who are alreadyreceiving opioid therapy for their underlyingpersistent cancer pain. Because dosage require-ments vary considerably, OTFC is available insix dosage strengths (200, 400, 600, 800, 1200,1600 µg) to allow individualization of therapy.Patients generally have access to one dosestrength of OTFC, which is established througha titration scheme that begins with a 200 µgunit for initial breakthrough pain and increasesas needed. If a patient’s fentanyl requirementchanges with time, it may be necessary to rees-tablish an appropriate dose strength throughtitration after therapy initiation. With only onedose strength of OTFC available to them atone time, however, patients can only titrate byaltering the time between dosages or consum-ing multiple doses at the same time. We hypoth-esize that this latter strategy would allowpatients to determine whether increasing theirdosage to the next available strength is appro-priate for their breakthrough pain needs.

The purpose of this study was to determinewhether the pharmacokinetic profile for twosimultaneously administered OTFC units wasequivalent to the profile from one unit that hadtwice the dose amount. To address this purpose,we compared the pharmacokinetic profile fromtwo 400 µg OTFC units given simultaneouslywith one 800 µg OTFC unit in volunteersubjects.

MethodsAfter Institutional Review Board approval

and volunteer consent, 12 healthy individualswere enrolled. Individuals were included in thestudy if they were between 18 and 50 years ofage, healthy by physical exam and medical his-tory, and had a body mass index of 20–28.Before beginning the study, each subject partic-ipated in a screening visit. The subjects hada medical and drug history taken, a completephysical examination, routine blood and urinetests, and female subjects received a serumHCG pregnancy test to confirm that they werenot pregnant.

The study used a single-center, open-labelrandomized crossover design. During the firststudy session, each subject was randomized toreceive either one 800 µg OTFC or two 400 µgOTFC to be consumed simultaneously. On theday of the study, subjects abstained from foodfor 6 hours and fluid intake for 2 hours beforethe start of the study. A venous catheter wasplaced in the volar forearm for blood samplingand a second catheter was placed in the oppo-site arm for intravenous hydration. An oral mu-cosal examination was performed to determineany local regions of irritation prior to drugadministration. Subjects were instructed todissolve the OTFC in their mouth over 15minutes. A timer was provided to assist the sub-ject in staying within the time frame. Subjectswere also instructed not to bite or chew theOTFC.

Venous blood samples were taken from onecatheter at baseline (5 minutes before receivingOTFC), and then at 5, 10, 15, 20, 25, 30, 35,40, 45, 50, 60, 75, and 90 minutes and subse-quently at 2, 3, 4, 6, 8, 12, and 24 hours afterthe administration of OTFC. Subjects remainedin the facility for a minimum of 12 hours follow-ing OTFC. The subjects returned to the facilityfor the 24-hour blood draw via direct venipunc-ture within 2 hours from the scheduled 24-hourblood draw time. The blood samples were cen-trifuged, and the plasma was removed andfrozen at �20� C for later analysis.

Serum fentanyl concentrations were deter-mined by a validated liquid chromatographic/mass spectrometric/mass spectrometric (LC/MS/MS) analytical method. Briefly, fentanyl and itsdeuterated internal standard were extracted bysolid phase extraction in a 96-well format. Theeluent from the extraction was injected intothe LC/MS/MS (Perkin Elmer Sciex API 365)using a turbo ion spray interface. Prior to theanalysis of study samples, the storage and ex-traction methods used were validated withspiked human serum quality control samples.The analysis method had a linear range of 0.05–100 ng/ml of fentanyl with a 0.05 ng/ml limitof quantitation.

Vital signs, blood pressure, heart rate, respira-tory rate, and percent oxygen saturation wereassessed at each time venous blood sampleswere taken. Oral mucosal examinations werecompleted before OTFC, and 30 minutes, 12

Vol. 26 No. 2 August 2003 745PK of Two Simultaneous OTFC vs. a Single Unit

hours, and 24 hours after receiving OTFC. In-quiries of any adverse events were conductedbefore subjects were released from the studyfacility and 24 hours after receiving OTFC. Forthe second dosing session, the subjects returnedto the testing facility after a one week washoutperiod and all steps were repeated with thealternate OTFC dosage form from the firstsession.

Non-compartmental pharmacokinetic pa-rameters were determined for each subject ateach dose using WinNonLin (Pharsight, Inc.Mountain View, CA). The data were modeledas an extravascular dose with plasma concentra-tion values. The primary noncompartmentalvalues of area under the curve (AUC), meanresidence time (MRT), maximum measureddrug concentration (Cmax), and time of peakconcentration measured (Tmax) were com-pared for each dose group using t-test withequal variances. Within subjects comparisonsbetween both doses were also made to evaluateany trends that exist for the primary parame-ters for a particular dose. The Wilcoxon signed

rank test was used for within subject comparisons.For all statistical analyses, a P value less than0.05 was considered significant.

ResultsTwelve subjects participated in the study, 5

women and 7 men. The mean age, weight, andheight for the participants were 31 years, 73 kg,and 175 cm respectively. All subjects completedboth study arms.

Individual and mean serum fentanyl concen-tration versus time profiles are shown in Figure1. Peak fentanyl concentrations were 1.09 ng/ml, with a range from 0.7–1.4 ng/ml in the two400 µg dose, and 1.10 ng/ml, with a range from0.6–2.5 ng/ml in the one 800 µg dose. As shownin Figure 1, the average concentration versustime profile is the same for both the two 400µg dose and one 800 µg dose groups. The meanvalues and standard error of the mean (SE)for AUC, MRT, Cmax, and Tmax are shown inFigure 2. AUCs showed no difference with a

Fig. 1. Mean and standard deviation of fentanyl plasma concentration versus time for one 800 µg OTFC dosecompared to the two 400 µg dose. The insert expands the first 2 hours of the plot. The plots show the pharmacoki-netic equivalence between these two dosages for the complete 24-hour study time period.

746 Vol. 26 No. 2 August 2003Lee et al.

Fig. 2. a) The average and standard error for Cmaxand Tmax as a function of dosage group. Therewere no statistically significant differences betweenthese parameters from each group. b) The mean andstandard error estimated for AUC and MRT as afunction of dosage group. As is seen with the data,there is no significant difference in these parametersbetween dosing groups.

mean of 8.2 ng/ml·hr (SE � 1.1) for the two400 µg dose and 7.2 ng/ml·hr (SE � 1.0) forthe one 800 µg dose. The mean residence timeshowed no significant difference betweendosage groups with 10.4 hours (SE � 1.3) forthe two 400 µg dose and 10.0 hours (SE � 1.3)for the one 800 µg group. There was no differ-ence in the elimination half-life between thetwo groups.

Asthenia, flushing, nausea, and headachewere the most common adverse events (AE)reported in both treatment groups. No seriousadverse events occurred during this trial andno subjects were discontinued due to AEs. Oralmucosal examinations performed during thetrial revealed no changes for any subject. As-thenia (a weak, tired, or heavy feeling) was ex-perienced by all 12 subjects. One episode wasconsidered severe and all resolved without ther-apy. Flushing was experienced by 6 subjects

(50%), nausea and vomiting were reported by6 subjects (50%), and pruritus was reportedby 4 subjects (33%). All of these events wereconsidered to be mild.

DiscussionThe results of this study demonstrate the bi-

oequivalence of fentanyl concentration levelsfollowing simultaneous consumption of two 400µg doses of OTFC compared to one 800 µgdose. There were no significant differences be-tween the two treatments in exposure time ofthe drug in the body (MRT), peak concentra-tion, and time to peak concentration. This sug-gests that total dose is more important thandosage form or surface area in determining thepharmacokinetics of transmucosally adminis-tered fentanyl.

These results are similar to other opioid dosetitration studies examining the pharmacokinet-ics of orally administered opioids.4,5 In a studyreview done by Kaiko et al., it was shown that two15-mg controlled-release oral morphine tabletswere the same as one 30-mg tablet, two 30-mgtablets equaled one 60-mg tablet, and three 30-mg tablets equaled one 100-mg tablet with re-spect to pharmacokinetic parameters.5 Themean plasma morphine versus time curves forthese three study comparison groups were verysimilar. The differences in AUC, Tmax, andCmax for these different dosage groups werenot statistically significant.

The adverse effect profile in this study wassimilar in other studies that administered OTFCto volunteers. In a dose proportionality studyby Streisand et al. using 12 healthy volunteers,adverse effects included pruritus (92%), nausea(1–83% depending on thedose), headache (17–67%), and vertigo (1–50%).6 These adverseeffects are presumably more common in the vol-unteer population compared to patients be-cause the volunteers are opioid naive. In a studyconsisting of 67 cancer patients by Portenoy etal., adverse effects included somnolence (28%),dizziness (14%), nausea (10%), and head-ache (5%).1

There was some variability in the fentanylconcentration-time profile, both within and be-tween subjects. Overall, however, there was nosignificant difference in relative bioavailabilitybetween subject groups, even though 10 out of

Vol. 26 No. 2 August 2003 747PK of Two Simultaneous OTFC vs. a Single Unit

12 subjects showed a slightly greater AUC withthe two 400 µg doses than the one 800 µgdose. From a theoretical perspective, it wouldbe reasonable to speculate that the increase insurface area of two 400 µg OTFC units couldcause a more rapid achievement of peak con-centration than a single 800 µg unit. Thoughthe time for maximal concentration was slightlyless for the one 800 µg unit group, the resultsshow that there was not a significant differencebetween these groups, implying that the in-creased surface area was not a critical factor.In a previous study, Streisand et al. showed thedose proportionality of OTFC with increasingdoses up to 1600 µg.6 Combined with the cur-rent study, these results suggest that two 200 µgdoses would be pharmacokinetically equivalentto one 400 µg dose and also that two 800 µgdoses would be equivalent to one 1600 µgdose.

The package insert for OTFC recommendsthat episodes of breakthrough cancer pain beinitially treated with a 200 µg unit. Thedosage level should be titrated until a dose thatprovides adequate analgesia with a single dos-age unit per breakthrough cancer pain epi-sode is determined. Patients should wait 15minutes after the previous unit has been com-pleted (30 minutes after the start of the previousunit) before administering a second dose. Iftreatment of several consecutive breakthroughcancer pain episodes requires more than oneunit per episode, an increase in dose to the nexthigher available strength should be consid-ered.7 Based on the results of this study, patientswho need to titrate their dosage of OTFCupward can simultaneously administer twoOTFC units at their current dose to see if thenext available dosage would be appropriate tomanage their breakthrough pain.

In conclusion, the pharmacokinetic profilefrom administering two 400 µg OTFC units is

thesame for one800 µg OTFC unit. Patients whoneed to titrate their dosage upward for break-through pain management can administer twounits simultaneously to see if the next dosageamount would be adequate for pain control.

AcknowledgmentsThis study was supported, in part, by a grant

from Cephalon, Inc. This study was conductedat the MDS Harris Laboratories, Lincoln, Ne-braska, and the University of Utah, Salt LakeCity, Utah.

References1. Portenoy RK, Payne R, Coluzzi P, et al. Oral trans-mucosal fentanyl citrate (OTFC) for the treatmentof breakthrough pain in cancer patients: a controlleddose titration study. Pain 1999;79:303–312.

2. Coluzzi PH, Schwartzberg L, Conroy JD, et al.Breakthrough cancer pain: a randomized trial com-paring oral transmucosal fentanyl citrate (OTFC)and morphine sulfate immediate release (MSIR).Pain 2001;91:123–130.

3. Streisand JB, Varvel JR, Stanski DR, et al. Absorp-tion and bioavailability of oral transmucosal fentanylcitrate. Anesthesiology 1991;75:223–229.

4. Benziger DP, Miotto J, Grandy RP, et al. A pharma-cokinetic/pharmacodynamic study of controlled-re-lease oxycodone. J Pain Symptom Manage 1997;13:75–82.

5. Kaiko RF, Grandy RP, Oshlack B, et al. The UnitedStates experience with oral controlled-release mor-phine (MS Contin tablets), Parts I and II. Review ofnine dose titration studies and clinical pharmacol-ogy of 15-mg, 30-mg, 60-mg, and 100-mg tabletstrengths in normal subjects. Cancer 1989;63:2348–2354.

6. Streisand JB, Busch MA, Egan TD, et al. Doseproportionality and pharmacokinetics of oral trans-mucosal fentanyl citrate. Anesthesiology 1998;88:305–309.

7. Cephalon I, Actiq Package Insert. 2002.