A Pharmacokinetic Study to Compare Two Simultaneous 400 µg Doses with a Single 800 µg Dose of Oral Transmucosal Fentanyl Citrate

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1 Vol. 26 No. 2 August 2003 Journal of Pain and Symptom Management 743 Original Article A Pharmacokinetic Study to Compare Two Simultaneous 400 µg Doses with a Single 800 µg Dose of Oral Transmucosal Fentanyl Citrate Maureen Lee, PharmD, Steven E. Kern, PhD, James C. Kisicki, MD, and Talmage D. Egan, MD College of Pharmacy (M.L.), Department of Pharmaceutics (S.E.K.), and Department of Anesthesiology (S.E.K., T.D.E.), University of Utah, Salt Lake City, Utah; and MDS Harris Laboratories (J.C.K.), Lincoln, Nebraska, USA Abstract It is unknown whether two smaller doses of oral transmucosal fentanyl citrate (OTFC) administered simultaneously are pharmacokinetically equivalent to an identical dose administered as a single unit. This issue has important practical implications when patients are attempting to identify the appropriate dosage of OTFC to control their pain. This open-label, randomized, crossover design study compared the pharmacokinetics of two simultaneously consumed 400 mg OTFC doses with one 800 mg OTFC dose in 12 healthy volunteers. The two treatments were pharmacokinetically equivalent. The maximum concentration produced for each dosage group (Cmax) was 1.09 ng/ml for two 400 mg dose 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 between the treatment groups in either the time to peak concentration (Tmax) or the mean residence time (MRT). The results demonstrate the bioequivalence of two 400 mg with one 800 mg OTFC units. J Pain Symptom Manage 2003;26: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Fentanyl, Actiq, OTFC, pharmacokinetics, bioequivalence, opioids Introduction Breakthrough pain is a transitory exacerbation of pain that occurs in addition to back- Address reprint requests to: Steven E. Kern, PhD, Department of Pharmaceutics, University of Utah, 421 Wakara Way, Suite 318, Salt Lake City, UT 84108, USA. Accepted for publication: December 12, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. ground or persistent pain in patients with chronic pain conditions. 1 Oral transmucosal fentanyl citrate (OTFC) has been shown to be an effective drug delivery method for breakthrough pain relief. 1,2 Fentanyl is absorbed from the OTFC unit into the circulation through the oral mucosa. This direct entry of fentanyl into the circulation avoids first pass metabolism, allowing the patient to obtain effective opioid levels more rapidly than oral administration. 3 The noninvasive nature of OTFC /03/$ see front matter doi: /s (03)

2 744 Lee et al. Vol. 26 No. 2 August 2003 gives the patient a convenient method to selftitrate analgesia in a relatively short period of time for the management of breakthrough pain. OTFC (Actiq, Cephalon Inc, West Chester, PA) is approved for the management of breakthrough cancer pain in patients who are already receiving opioid therapy for their underlying persistent cancer pain. Because dosage requirements vary considerably, OTFC is available in six dosage strengths (200, 400, 600, 800, 1200, 1600 µg) to allow individualization of therapy. Patients generally have access to one dose strength of OTFC, which is established through a titration scheme that begins with a 200 µg unit for initial breakthrough pain and increases as needed. If a patient s fentanyl requirement changes with time, it may be necessary to reestablish an appropriate dose strength through titration after therapy initiation. With only one dose strength of OTFC available to them at one time, however, patients can only titrate by altering the time between dosages or consuming multiple doses at the same time. We hypothesize that this latter strategy would allow patients to determine whether increasing their dosage to the next available strength is appropriate for their breakthrough pain needs. The purpose of this study was to determine whether the pharmacokinetic profile for two simultaneously administered OTFC units was equivalent to the profile from one unit that had twice the dose amount. To address this purpose, we compared the pharmacokinetic profile from two 400 µg OTFC units given simultaneously with one 800 µg OTFC unit in volunteer subjects. Methods After Institutional Review Board approval and volunteer consent, 12 healthy individuals were enrolled. Individuals were included in the study if they were between 18 and 50 years of age, healthy by physical exam and medical history, and had a body mass index of Before beginning the study, each subject participated in a screening visit. The subjects had a medical and drug history taken, a complete physical examination, routine blood and urine tests, and female subjects received a serum HCG pregnancy test to confirm that they were not pregnant. The study used a single-center, open-label randomized crossover design. During the first study session, each subject was randomized to receive either one 800 µg OTFC or two 400 µg OTFC to be consumed simultaneously. On the day of the study, subjects abstained from food for 6 hours and fluid intake for 2 hours before the start of the study. A venous catheter was placed in the volar forearm for blood sampling and a second catheter was placed in the opposite arm for intravenous hydration. An oral mucosal examination was performed to determine any local regions of irritation prior to drug administration. Subjects were instructed to dissolve the OTFC in their mouth over 15 minutes. A timer was provided to assist the subject in staying within the time frame. Subjects were also instructed not to bite or chew the OTFC. Venous blood samples were taken from one catheter at baseline (5 minutes before receiving OTFC), and then at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, and 90 minutes and subsequently at 2, 3, 4, 6, 8, 12, and 24 hours after the administration of OTFC. Subjects remained in the facility for a minimum of 12 hours following OTFC. The subjects returned to the facility for the 24-hour blood draw via direct venipuncture within 2 hours from the scheduled 24-hour blood draw time. The blood samples were centrifuged, and the plasma was removed and frozen at 20 C for later analysis. Serum fentanyl concentrations were determined by a validated liquid chromatographic/ mass spectrometric/mass spectrometric (LC/MS/ MS) analytical method. Briefly, fentanyl and its deuterated internal standard were extracted by solid phase extraction in a 96-well format. The eluent from the extraction was injected into the LC/MS/MS (Perkin Elmer Sciex API 365) using a turbo ion spray interface. Prior to the analysis of study samples, the storage and extraction methods used were validated with spiked human serum quality control samples. The analysis method had a linear range of ng/ml of fentanyl with a 0.05 ng/ml limit of quantitation. Vital signs, blood pressure, heart rate, respiratory rate, and percent oxygen saturation were assessed at each time venous blood samples were taken. Oral mucosal examinations were completed before OTFC, and 30 minutes, 12

3 Vol. 26 No. 2 August 2003 PK of Two Simultaneous OTFC vs. a Single Unit 745 hours, and 24 hours after receiving OTFC. Inquiries of any adverse events were conducted before subjects were released from the study facility and 24 hours after receiving OTFC. For the second dosing session, the subjects returned to the testing facility after a one week washout period and all steps were repeated with the alternate OTFC dosage form from the first session. Non-compartmental pharmacokinetic parameters were determined for each subject at each dose using WinNonLin (Pharsight, Inc. Mountain View, CA). The data were modeled as an extravascular dose with plasma concentration values. The primary noncompartmental values of area under the curve (AUC), mean residence time (MRT), maximum measured drug concentration (Cmax), and time of peak concentration measured (Tmax) were compared for each dose group using t-test with equal variances. Within subjects comparisons between both doses were also made to evaluate any trends that exist for the primary parameters for a particular dose. The Wilcoxon signed rank test was used for within subject comparisons. For all statistical analyses, a P value less than 0.05 was considered significant. Results Twelve subjects participated in the study, 5 women and 7 men. The mean age, weight, and height for the participants were 31 years, 73 kg, and 175 cm respectively. All subjects completed both study arms. Individual and mean serum fentanyl concentration versus time profiles are shown in Figure 1. Peak fentanyl concentrations were 1.09 ng/ ml, with a range from ng/ml in the two 400 µg dose, and 1.10 ng/ml, with a range from ng/ml in the one 800 µg dose. As shown in Figure 1, the average concentration versus time profile is the same for both the two 400 µg dose and one 800 µg dose groups. The mean values and standard error of the mean (SE) for AUC, MRT, Cmax, and Tmax are shown in Figure 2. AUCs showed no difference with a Fig. 1. Mean and standard deviation of fentanyl plasma concentration versus time for one 800 µg OTFC dose compared to the two 400 µg dose. The insert expands the first 2 hours of the plot. The plots show the pharmacokinetic equivalence between these two dosages for the complete 24-hour study time period.

4 746 Lee et al. Vol. 26 No. 2 August 2003 (50%), nausea and vomiting were reported by 6 subjects (50%), and pruritus was reported by 4 subjects (33%). All of these events were considered to be mild. Fig. 2. a) The average and standard error for Cmax and Tmax as a function of dosage group. There were no statistically significant differences between these parameters from each group. b) The mean and standard error estimated for AUC and MRT as a function of dosage group. As is seen with the data, there is no significant difference in these parameters between dosing groups. mean of 8.2 ng/ml hr (SE 1.1) for the two 400 µg dose and 7.2 ng/ml hr (SE 1.0) for the one 800 µg dose. The mean residence time showed no significant difference between dosage groups with 10.4 hours (SE 1.3) for the two 400 µg dose and 10.0 hours (SE 1.3) for the one 800 µg group. There was no difference in the elimination half-life between the two groups. Asthenia, flushing, nausea, and headache were the most common adverse events (AE) reported in both treatment groups. No serious adverse events occurred during this trial and no subjects were discontinued due to AEs. Oral mucosal examinations performed during the trial revealed no changes for any subject. Asthenia (a weak, tired, or heavy feeling) was experienced by all 12 subjects. One episode was considered severe and all resolved without therapy. Flushing was experienced by 6 subjects Discussion The results of this study demonstrate the bioequivalence of fentanyl concentration levels following simultaneous consumption of two 400 µg doses of OTFC compared to one 800 µg dose. There were no significant differences between the two treatments in exposure time of the drug in the body (MRT), peak concentration, and time to peak concentration. This suggests that total dose is more important than dosage form or surface area in determining the pharmacokinetics of transmucosally administered fentanyl. These results are similar to other opioid dose titration studies examining the pharmacokinetics of orally administered opioids. 4,5 In a study review done by Kaiko et al., it was shown that two 15-mg controlled-release oral morphine tablets were the same as one 30-mg tablet, two 30-mg tablets equaled one 60-mg tablet, and three 30- mg tablets equaled one 100-mg tablet with respect to pharmacokinetic parameters. 5 The mean plasma morphine versus time curves for these three study comparison groups were very similar. The differences in AUC, Tmax, and Cmax for these different dosage groups were not statistically significant. The adverse effect profile in this study was similar in other studies that administered OTFC to volunteers. In a dose proportionality study by Streisand et al. using 12 healthy volunteers, adverse effects included pruritus (92%), nausea (1 83% depending on the dose), headache (17 67%), and vertigo (1 50%). 6 These adverse effects are presumably more common in the volunteer population compared to patients because the volunteers are opioid naive. In a study consisting of 67 cancer patients by Portenoy et al., adverse effects included somnolence (28%), dizziness (14%), nausea (10%), and headache (5%). 1 There was some variability in the fentanyl concentration-time profile, both within and between subjects. Overall, however, there was no significant difference in relative bioavailability between subject groups, even though 10 out of

5 Vol. 26 No. 2 August 2003 PK of Two Simultaneous OTFC vs. a Single Unit subjects showed a slightly greater AUC with the two 400 µg doses than the one 800 µg dose. From a theoretical perspective, it would be reasonable to speculate that the increase in surface area of two 400 µg OTFC units could cause a more rapid achievement of peak concentration than a single 800 µg unit. Though the time for maximal concentration was slightly less for the one 800 µg unit group, the results show that there was not a significant difference between these groups, implying that the increased surface area was not a critical factor. In a previous study, Streisand et al. showed the dose proportionality of OTFC with increasing doses up to 1600 µg. 6 Combined with the current study, these results suggest that two 200 µg doses would be pharmacokinetically equivalent to one 400 µg dose and also that two 800 µg doses would be equivalent to one 1600 µg dose. The package insert for OTFC recommends that episodes of breakthrough cancer pain be initially treated with a 200 µg unit. The dosage level should be titrated until a dose that provides adequate analgesia with a single dosage unit per breakthrough cancer pain episode is determined. Patients should wait 15 minutes after the previous unit has been completed (30 minutes after the start of the previous unit) before administering a second dose. If treatment of several consecutive breakthrough cancer pain episodes requires more than one unit per episode, an increase in dose to the next higher available strength should be considered. 7 Based on the results of this study, patients who need to titrate their dosage of OTFC upward can simultaneously administer two OTFC units at their current dose to see if the next available dosage would be appropriate to manage their breakthrough pain. In conclusion, the pharmacokinetic profile from administering two 400 µg OTFC units is thesame for one 800 µg OTFC unit. Patients who need to titrate their dosage upward for breakthrough pain management can administer two units simultaneously to see if the next dosage amount would be adequate for pain control. Acknowledgments This study was supported, in part, by a grant from Cephalon, Inc. This study was conducted at the MDS Harris Laboratories, Lincoln, Nebraska, and the University of Utah, Salt Lake City, Utah. References 1. Portenoy RK, Payne R, Coluzzi P, et al. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study. Pain 1999;79: Coluzzi PH, Schwartzberg L, Conroy JD, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001;91: Streisand JB, Varvel JR, Stanski DR, et al. Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991;75: Benziger DP, Miotto J, Grandy RP, et al. A pharmacokinetic/pharmacodynamic study of controlled-release oxycodone. J Pain Symptom Manage 1997;13: Kaiko RF, Grandy RP, Oshlack B, et al. The United States experience with oral controlled-release morphine (MS Contin tablets), Parts I and II. Review of nine dose titration studies and clinical pharmacology of 15-mg, 30-mg, 60-mg, and 100-mg tablet strengths in normal subjects. Cancer 1989;63: Streisand JB, Busch MA, Egan TD, et al. Dose proportionality and pharmacokinetics of oral transmucosal fentanyl citrate. Anesthesiology 1998;88: Cephalon I, Actiq Package Insert