- Email: [email protected]
Effect of Modulated Electrohyperthermia on the Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers
Clinical Therapeutics/Volume 38, Number 12, 2016
Original Research
Effect of Modulated Electrohyperthermia on the Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers Sun Young Lee, MD, PhD1,2; and Min-Gul Kim, MD, PhD2,3 1
Department of Radiation Oncology, Hospital, Jeonju, Jeonbuk, Republic of Korea; 2Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; and 3Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Republic of Korea ABSTRACT
INTRODUCTION
Purpose: This study aimed to determine whether changes occur in fentanyl absorption and disposition when administered in conjunction with modulated electrohyperthermia (mEHT) treatment. Methods: A randomized, single-dose, crossover, open-label study was used to investigate the effect of mEHT on the pharmacokinetic properties of fentanyl in 12 healthy volunteers. The 12 healthy volunteers were each administered a single dose of oral transmucosal fentanyl citrate (OTFC) or a single dose of OTFC with mEHT. mEHT was performed on the abdomen for 1 hour. Blood samples were collected for 24 hours after dosing. The temperature of the abdominal skin surface was assessed before dosing and at 10, 20, and 60 minutes after dosing. Findings: Geometric mean ratios (ratio of fentanyl with mEHT to fentanyl alone) for the Cmax and AUC0–last were 1.20 (90% CI, 1.09–1.32) and 1.15 (90% CI, 0.99–1.33), respectively. The mean temperature of the abdominal skin surface increased by approximately 41C. Implications: There was an increase in the overall exposure to the drug without implications of any clinical significance. OTFC can be administered without limitations in combination with mEHT, and it is not necessary to modify the dosing regimen. cris.nih.go,kr Identifier: KCT0001286. (Clin Ther. 2016;38:2548–2554) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: clinical trial, electrohyperthermia, fentanyl, pharmacokinetics, temperature of the abdominal skin surface.
Hyperthermia has long been used for pain management, even in ancient medical practices.1 A higher local tissue temperature induces vasodilation, which enables greater oxygen transfer due to increased local blood flow and reduces pain.2 A higher blood flow increases the delivery of nutrients and eliminates carbon dioxide, metabolic waste, and inflammatory chemical mediators. Increased local blood flow also affects the treatment efficacy of the heated target. Modulated electrohyperthermia (mEHT) is the next-generation medical innovation that delivers selective, controlled, and deep energy treatments using the capacitive-coupled energy of 13.56-MHz amplitude-modulated radiofrequency for cancer therapy.3,4 Malignant cells are selectively heated, affecting the cell membranes5 and inducing apoptosis at mild temperatures (r42°C).4,6 This treatment promotes immunogenic cell death.7,8 The mEHT does not cause pain and causes few adverse effects (AEs), resulting in improved efficacy and quality of life.9 Moreover, patients treated with mEHT have reported pain relief10 and, as a result, have used decreased doses of analgesics.11 Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia.12 Fentanyl binds to μ-opioid receptors in various locations of the central nervous system and relieves pain by increasing pain
Accepted for publication October 25, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.10.012 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.
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S.Y. Lee and M.-G. Kim thresholds, changing pain sensations, and inhibiting ascending pain pathways.13 Fentanyl is generally considered 50 to 100 times more potent than morphine.13 The fentanyl citrate oral transmucosal lozenge* is a solid formulation of fentanyl citrate delivered on a plastic stick. Generic fentanyl citrate is a form of oral transmucosal fentanyl citrate (OTFC). The absorption pharmacokinetic properties of OTFC works via initial rapid absorption through the buccal mucosa and prolonged absorption through the gastrointestinal (GI) tract.14 The peak blood concentration is observed 20 to 40 minutes after the initiation of OTFC application.13 Thus, OTFC is used to treat breakthrough pain in patients with cancer who already received and are tolerant to around-the-clock opioid therapies for underlying persistent cancer pain.14,15 The analgesic effect of OTFC is related to the blood concentration of fentanyl at a range of 0.3 to 1.2 ng/mL, and levels in excess of 10 to 20 ng/mL are associated with surgical anesthesia and respiratory depression.16 OTFC is often consumed during mEHT therapy. The heat with radiation would be influenced by the heatinduced changes in regional blood flow.17 mEHT may affect the pharmacokinetic properties of fentanyl because of changes in the regional blood flow. The unexpected AEs can be caused by changes in the fentanyl concentration. Therefore, we examined the effects of mEHT on the pharmacokinetic properties of fentanyl in healthy volunteers.
SUBJECTS AND METHODS This study was approved by the Ministry of Food and Drug Safety and the Institutional Review Board of Chonbuk National University Hospital. This study was conducted according to the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki and according to the Good Clinical Practice guidelines. Written informed consent was obtained from each participant before screening, and a detailed explanation of the study was provided. Healthy male and female volunteers aged 19 to 55 years with body mass indexes ranging from 17.5 to 30.5 kg/m2 were enrolled in the study. The health of Trademark: ACTIQs (Cephalon, Frazer, Pennsylvania).
*
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each subject was confirmed via physical examinations, measurements of vital signs, and clinical laboratory assessments (ie, hematology, biochemistry, serology, urinalysis, and urine human chorionic gonadotropin tests for females of childbearing potential). Subjects were excluded if they had taken any prescription medications or over-the-counter drugs within 10 days before the first administration of OTFC. Subjects were also excluded if their sitting blood pressure decreased in the following ranges during the screening procedure: systolic blood pressure Z140 mm Hg and diastolic blood pressure Z90 mm Hg. Subjects were required to abstain from taking any medication without prior consent of the investigator and from drinking alcohol, smoking, and consuming food or beverages that contained caffeine during the study period. All subjects were asked to abstain from taking food or beverages that contained grapefruit for 7 days before the first administration to the discharge of the second admission. This study was conducted as an open-label, randomized-sequence, 2-period, 2-treatment, singledose, 2-way crossover trial at the Clinical Trial Center of Chonbuk National University Hospital, Jeonju, Republic of Korea. All subjects were randomly assigned to 1 of 2 treatment sequence groups: AB or BA. The 2 treatments were as follows: (A) 0.3142 mg of OTFC (Hyundai Pharmaceutical Inc, Seoul, Republic of Korea), which is equivalent to 0.2 mg of fentanyl free base and (B) 0.3142 mg of OTFC with mEHT. Each sequence group consisted of 6 subjects. Each period was followed by a 1-week washout period. On the first day of each period, all subjects were administered OTFC on day 1 at the clinical facility. OTFC was presented as a sweetened lozenge with an integral oromucosal applicator (unit) for oral administration by sucking not chewing. A unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed because the generally observed 50% bioavailability of OTFC is divided equally between rapid transmucosal and slower GI absorption. Subjects should place the OTFC unit in their mouths between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. Subjects were instructed to consume the total dose within 15 minutes. All subjects received OTFC within 15 minutes. The unit was not to be bitten, chewed, or swallowed. Each
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Clinical Therapeutics mEHT treatment was applied 30 minutes after OTFC administration. Blood samples for pharmacokinetic analyses were collected before OTFC dosing (baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after OTFC dosing for a total of 13 blood samples. The blood was collected using heparinized tubes, which were temporarily stored in an icebox. For processing, the tubes were centrifuged for 10 minutes at 1811g rpm at 41C within 1 hour after sampling. One milliliter of plasma was transferred into each of 3 polypropylene tubes, and all samples were stored at 701C until further analysis. The plasma concentrations of fentanyl were analyzed using a validated LC-MS/MS method. multiple reaction monitoring (MRM) transition of m/z 337.2 - 188.1 and 452.4 - 344.4 were chosen for fentanyl and the internal standard (doxazosin). A Luna C18 (50 2.0 mm; particle size, 5 μm) analytical column was used. The mobile phase used 0.1% formic acid in water and acetonitrile. A calibration curve covering the range of 0.1 to 200 mg/mL was constructed. The calibration curves were linear over the calibration concentration range (r Z 0.9988). The intra-assay accuracy and precision were 92.7% to 108.8% and 3.0% to 12.2%, whereas the interassay accuracy and precision were 95.6% to 103.6% and 1.7% to 15.9%, respectively. Individual pharmacokinetic parameters were obtained by noncompartmental methods using Phoenix WinNonlin 6.3 software (Pharsight Corporation, Sunnyvale, California). The Cmax and Tmax were directly obtained from plasma concentration-time curves. The AUC0–last was calculated using the linear trapezoidal rule. The AUC0–1 was calculated using the equation AUC0–last þ (C0–last/ke), where AUC0–last was the area under the plasma concentration time curve to the last sampling time, C0–last was the last measurable concentration, and ke was the slope of the linear regression of the log-transformed plasma concentration time in the terminal phase. The CL/F was calculated by the equation (CL/F ¼ dose/AUC0–1), and the Vd/F was calculated by the equation (Vd/F ¼ dose/keAUC0–1). Thirty minutes after beginning OTFC administration, mEHT was applied for 60 minutes on abdomen area using an EHY2000 clinical heating device (Oncotherm GmbH, Troisdorf, Germany) with a carrier frequency of 13.56 MHz. mEHT was amplitudemodulated according to a time-fractal pattern.18
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The subjects were positioned in a supine position on a water-mattress electrode. A circular upper electrode, 30 cm in diameter, was coupled over the abdominal area covering the entire liver, both kidneys, and at least 90% of the intestines. The power output was 100 W for the first 10 minutes, 120 W for the following 10 minutes, and 150 W for the remaining treatment time. The device was calibrated before each treatment. The abdominal skin surface temperature was assessed before dosing and 10, 20, and 60 minutes after OTFC dosing. Tolerability was assessed by evaluating the physical examination findings, vital sign measurements, and laboratory test results. AEs were monitored throughout the study. AEs were determined by investigator inquiries and spontaneous patient reports. Statistical analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, North Carolina). Descriptive statistics were used to summarize pharmacokinetic data. At a 5% significance level, ANOVA was used to compare pharmacokinetic parameters. The point estimates and 90% CIs of the ratios of the geometric means ratios (ratio of fentanyl with mEHT to fentanyl alone) of log-transformed Cmax and AUC0–last were compared. Because this was a descriptive study to evaluate potential drug interactions with mEHT treatment, no formal sample size estimation was performed for pharmacokinetic evaluations. Intraindividual %CVs in Cmax and AUC of fentanyl were assumed to not exceed 10%.19 A total sample size of 12 achieves an 98% power at a 5% significance level when the true ratio of the means is 1.05 and the %CV is 10%.
RESULTS Ten male and 2 female subjects (mean [SD] age, 28.9 [8.7] years; mean [SD] height, 172.6 [5.5] cm; and mean [SD] weight, 68.2 [9.0] kg) were eligible for the study and were assigned to the relevant sequence groups using a randomization process (Table I). All subjects completed the study according to the protocol. The pharmacokinetic parameters of fentanyl were evaluated and are summarized in Table II. The mean plasma concentration-time profiles are presented in Figure 1. The mean Cmax and AUC0–last of fentanyl were 0.38 ng/mL and 1.32 h ∙ ng/mL, respectively, for the fentanyl with mEHT treatment. The mean Cmax and
Volume 38 Number 12
S.Y. Lee and M.-G. Kim
Table I. Demographic characteristics of the 12 study subjects. Age, y
Height, cm
Weight, kg
BMI, kg/m2
28.9 (8.7) 19–51
172.5 (5.5) 158.1–180.5
68.2 (9.0) 56.5–84.4
22.9 (2.6) 19.3–26.6
Characteristic Mean (SD) Range BMI ¼ body mass index.
AUC0–last of fentanyl were 0.32 ng/mL and 1.28 h ∙ ng/mL, respectively, for the fentanyl alone treatment. The Tmax and elimination t½ values of fentanyl were similar for the 2 treatments. The point estimates of the ratios of the geometric means (ratio of test to reference) of the Cmax and AUC0–last of fentanyl administered in the fentanyl with mEHT group and fentanyl alone group were 1.20 (90% CI, 1.09–1.32) and 1.15 (90% CI, 0.99–1.33), respectively (Table III). The intrasubject %CV of the Cmax and AUC0–last of fentanyl were 13.1% and 20.6%, respectively. The ANOVA results revealed no carryover effect of any pharmacokinetic parameter. The temperature of the abdominal skin surface underneath the upper electrode before heating ranged from 36.41C to 36.91C (mean [SD], 36.51C [0.14]1C) and increased to 39.81C to 40.91C (mean [SD], 40.51C [0.36]1C). The mean surface temperature increased by approximately 41C (Figure 2).
Tolerability was assessed in 12 subjects who received the fentanyl treatments. A total of 8 AEs were reported among 5 subjects. The AEs were asthenia (3 cases) and nausea (2 cases) for the fentanyl treatment and asthenia (2 cases) and headache (1 case) for the fentanyl with mEHT treatment. All the subjects with AEs recovered within 5 hours without sequelae, and no serious AEs were observed. In addition, the results of the physical examinations, vital sign measurements, and clinical laboratory tests indicated that no clinically significant changes occurred during the study.
DISCUSSION Typically, approximately 25% of the total dose of OTFC is rapidly absorbed through the buccal mucosa and becomes systemically available.20 The absorption of OTFC is more rapid compared with other oral tablets (the pain is relieved within 15 minutes after
Table II. Pharmacokinetic parameters after a single oral administration of the 2 treatments in the 12 study subjects. Pharmacokinetic Parameter Cmax, ng/mL AUC0–last, h ∙ ng/mL AUC0–1, h ∙ ng/mL‡ Tmax, h t1/2, h‡ CL/F, L/h‡ Vd/F, L‡
Fentanyl (0.2 mg) with mEHT* 0.38 1.32 2.38 1.48 3.63 96.01 454.77
(0.09) (0.68) (0.87) (0.66) (1.42 (41.42) (198.89)
Fentanyl (0.2 mg) Alone* 0.32 1.28 2.80 1.56 5.47 87.96 598.84
(0.10) (1.13) (1.74) (0.66) (2.96) (36.46) (200.64)
P† 0.1837 0.4529 0.8480 0.7642 0.2774 0.8480 0.0845
mEHT ¼ modulated electrohyperthermia. * The values are presented as the arithmetic means (SDs). † The P values were calculated with the Wilcoxon rank-sum test. ‡ n ¼ 7; the elimination rate constant of 5 subjects cannot be calculated.
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Clinical Therapeutics
41 Fentanyl 0.2 mg Fentanyl 0.2 mg with modulated electro hyperthermia
0.4
0.3
0.2
Fentanyal 0.2 mg Fentanyal 0.2 mg with modulated electro hyperthermia
40 Temperature (°C)
Plasma Concentration of Fentanyl (ng/mL)
0.5
39
38
0.1
37 0.0 0
6
12
18
24
36 0
Time (h)
10
20
30
40
50
60
Time (min)
Figure 1. Plasma concentration-time profiles of fentanyl after 0.3142 mg of oral transmucosal fentanyl citrate (as 0.2 mg of fentanyl) with modulated electrohyperthermia treatment and 0.3142 mg of oral transmucosal fentanyl citrate alone treatment.
administration),21 and its analgesic effect appears as rapidly as its intravenous administration.22 The remaining 75% of the total OTFC dose is slowly absorbed through the GI tract.23 Approximately onethird of this amount (ie, 25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.22 In our study, the mean fentanyl plasma concentration-time curves displayed double peaks, which are characteristic of OTFC administration. The bioavailability of fentanyl is divided equally between rapid transmucosal absorption and slower GI absorption.14,24 Fentanyl is primarily (490%) metabolized in the liver and has a high extraction ratio,14,25–28 which makes it unlikely
Figure 2. The temperature of the abdominal skin surface after 0.3142 mg of oral transmucosal fentanyl citrate (as 0.2 mg of fentanyl) with modulated electrohyperthermia treatment and 0.3142 mg of oral transmucosal fentanyl citrate alone treatment.
to have clinically significant pharmacokinetic drug interactions during elimination.29 However, the clearance of high-extraction drugs, such as fentanyl, is affected by changes in hepatic blood flow.30 This study was designed to determine the maximum effect of slower fentanyl (GI) absorption through a 30-minute mEHT treatment beginning 60 minutes after the oral administration of OTFC. As the hyperthermia treatment progressed, the Cmax of fentanyl might be increased because of increased absorption through the digestive tract. Even after the oral dosing of fentanyl ended, the drug absorption continued to increase. Generally, orally administered drugs are
Table III. Statistical analysis of fentanyl pharmacokinetic parameters in the 12 study subjects. Geometric LS Mean Pharmacokinetic Parameter Cmax, ng/mL AUC0–last, h ∙ ng/mL
Fentanyl (0.2 mg) With mEHT
Fentanyl (0.2 mg) Alone
Geometric LS Mean Ratio (90% CI)
0.37 1.18
0.31 1.03
1.20 (1.09–1.32) 1.15 (0.99–1.33)
LS ¼ least squares; mEHT ¼ modulated electrohyperthermia.
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S.Y. Lee and M.-G. Kim absorbed through the GI tract via the blood supply. mEHT treatments increase the temperature of the targeted region, inducing increased blood flow.11 Thus, abdominal mEHT induces increased blood flow in the abdominal region and affects the pharmacokinetic properties of orally administered drugs.31 Our results reveal that slightly increased Cmax indicated an increased drug absorption rate by mEHT. However, considering that the increase in Cmax was not significant, these findings are not expected to influence the expected therapeutic effect of fentanyl. The changes in the AUC did not affect the metabolism or the excretion of the drug during hyperthermia, and hyperthermia might not affect the overall therapeutic efficacy of fentanyl. This study has some limitations. The study was conducted only on heathy subjects. Intestinal or hepatic blood flow also remains to be measured during the hyperthermia treatment progress. Therefore, additional studies in patients with cancer might be beneficial for evaluating the pharmacokinetic properties of fentanyl and measuring intestinal or haptic blood flow.
CONCLUSIONS In conclusion, few differences were observed in the overall disposition of the drug; thus, the combination of fentanyl and mEHT treatment may not have had any clinical significance. Therefore, OTFC can be administered with or without mEHT, and a modification of the dosing regimen is unnecessary.
ACKNOWLEDGMENTS Sun Young Lee contributed to the data collection as a principal investigator and wrote the manuscript. MinGul Kim contributed to the data collection as a coinvestigator, participated in the data analyses, and wrote and reviewed the manuscript.
FUNDING SOURCES This study was supported by Hyundai Pharmaceutical, Inc., Seoul, Republic of Korea.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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REFERENCES 1. Seegenschmiedt MH, Vernon CC. A historical perspective on hyperthermia in oncology. In: Seegenschmiedt MH, Fessenden P, Vernon CC, eds. Thermoradiotherapy and thermochemotherapy. New York: Springer; 1995:3–44. 2. Kosaka M, Sugahara T, Schmidt KL, Simon E. Thermotherapy for neoplasia, inflammation, and pain. Berlin: Springer Science & Business Media; 2013. 3. Szasz A, Szasz N, Szasz O. Oncothermia: Principles and Practices. Rotterdam: Springer Netherlands; 2010. 4. Tsang YW, Huang CC, Yang KL, et al. Improving immunological tumor microenvironment using electrohyperthermia followed by dendritic cell immunotherapy. BMC Cancer. 2015;15:708. 5. Szasz A, Vincze GY, Szasz O, Szasz N. An energy analysis of extracellular hyperthermia. Electromagn Biol Med. 2003;22:103–115. 6. Meggyeshazi N, Andocs G, Balogh L, et al. DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. Strahlenther Onkol. 2014;190:815–822. 7. Andocs G, Meggyeshazi N, Balogh L, et al. Upregulation of heat shock proteins and the promotion of damageassociated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress Chaperones. 2015;20:37–46. 8. Andocs G, Meggyeshazi N, Okamoto Y, et al. Bystander effect of oncothermia. Conf Pap Med. 2013;2013:953482. 9. Andocs G, Szasz O, Szasz A. Oncothermia treatment of cancer: from the laboratory to clinic. Electromagnetic biol Med. 2009;28:148–165. 10. Szasz A. Current status of oncothermia therapy for lung cancer. Korean J Thorac Cardiovasc Surg. 2014;47:77. 11. Jeung TS, Ma SY, Yu J, Lim S. Cases that respond to oncothermia monotherapy. Conf Pap Sci. 2013;2013: 392480. 12. Bagley JR, Wynn RL, Rudo FG, et al. New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties. J med chem. 1989;32:663–671. 13. Mystakidou K, Katsouda E, Parpa E, et al. Oral transmucosal fentanyl citrate: overview of pharmacological and clinical characteristics. Drug Deliv. 2006;13:269–276. 14. ACTIQ Full Prescribing Information. Frazer, PA: Cephalon Inc; 2011. 15. Christie JM, Simmonds M, Patt R, et al. Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain. J Clin Oncol. 1998;16:3238–3245. 16. EMC. Abstral sublingual tablets summary of product characteristics. Kyowa Kirin Ltd, United Kingdom.
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https://www.medicines.org.uk/emc/ medicine/21371. Accessed October 4, 2016. Song CW. Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Res. 1984; 44:4721s–4730s. Hager E, Sahinbas H, Groenemeyer D, Migeod F. Prospective phase II trial for recurrent high-grade gliomas with capacitive coupled low radiofrequency (LRF) hyperthermia. ASCO Ann Mtg Proc. 2008;262008: 2047. Vasisht N, Gever LN, Tagarro I, Finn AL. Single‐dose pharmacokinetics of fentanyl buccal soluble film. Pain Medicine. 2010;11:1017–1023. Lichtor JL, Sevarino FB, Joshi GP, et al. The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain. Anesth Analg. 1999;89:732. Streisand JB, Varvel JR, Stanski DR, et al. Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology. 1991;75:223–229. Smith H. A comprehensive review of rapid-onset opioids for breakthrough pain. CNS Drugs. 2012;26: 509–535. Mystakidou K, Tsilika E, Tsiatas M, Vlahos L. Oral transmucosal fentanyl citrate in cancer pain management: a practical application of nanotechnology. Int J Nanomed. 2007; 2:49–54. Twycross R, Prommer EE, Mihalyo M, Wilcock A. Fentanyl (transmucosal). J Pain Symptom Manag. 2012; 44:131–149. Bower S, Hull C. Comparative pharmacokinetics of fentanyl and alfentanil. Br J Anaesth. 1982;54:871–877. Mather LE, Woodhouse A, Ward ME, et al. Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol. 1998;46:37–43. Palkama VJ, Neuvonen PJ, Olkkola KT. The CYP 3A4 inhibitor itraconazole has
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no effect on the pharmacokinetics of iv fentanyl. Br J Anaesth. 1998;81: 598–600. 28. Olkkola KT, Palkama VJ, Neuvonen PJ. Ritonavir's role in reducing fentanyl clearance and prolonging its half-life. Anesthesiology. 1999;91:681–685. 29. Hemmings HC, Hopkins PM. Foundations of anesthesia: basic sciences for clinical practice. Philadelphia: Elsevier Health Sciences; 2006.
30. Rowland M, Tozer TN. Clinical pharmacokinetics/pharmacodynamics. Philadelphia: Lippincott Williams and Wilkins; 2005. 31. Lee SY, Kim MG. The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: a randomised, single-dose, crossover open-label study. Int J hyperthermia. 2015;31:869–874.
Address correspondence to: Min-Gul Kim, MD, PhD, Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea. E-mail: [email protected]
Volume 38 Number 12
Original Research
Effect of Modulated Electrohyperthermia on the Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers Sun Young Lee, MD, PhD1,2; and Min-Gul Kim, MD, PhD2,3 1
Department of Radiation Oncology, Hospital, Jeonju, Jeonbuk, Republic of Korea; 2Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; and 3Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Republic of Korea ABSTRACT
INTRODUCTION
Purpose: This study aimed to determine whether changes occur in fentanyl absorption and disposition when administered in conjunction with modulated electrohyperthermia (mEHT) treatment. Methods: A randomized, single-dose, crossover, open-label study was used to investigate the effect of mEHT on the pharmacokinetic properties of fentanyl in 12 healthy volunteers. The 12 healthy volunteers were each administered a single dose of oral transmucosal fentanyl citrate (OTFC) or a single dose of OTFC with mEHT. mEHT was performed on the abdomen for 1 hour. Blood samples were collected for 24 hours after dosing. The temperature of the abdominal skin surface was assessed before dosing and at 10, 20, and 60 minutes after dosing. Findings: Geometric mean ratios (ratio of fentanyl with mEHT to fentanyl alone) for the Cmax and AUC0–last were 1.20 (90% CI, 1.09–1.32) and 1.15 (90% CI, 0.99–1.33), respectively. The mean temperature of the abdominal skin surface increased by approximately 41C. Implications: There was an increase in the overall exposure to the drug without implications of any clinical significance. OTFC can be administered without limitations in combination with mEHT, and it is not necessary to modify the dosing regimen. cris.nih.go,kr Identifier: KCT0001286. (Clin Ther. 2016;38:2548–2554) & 2016 Elsevier HS Journals, Inc. All rights reserved. Key words: clinical trial, electrohyperthermia, fentanyl, pharmacokinetics, temperature of the abdominal skin surface.
Hyperthermia has long been used for pain management, even in ancient medical practices.1 A higher local tissue temperature induces vasodilation, which enables greater oxygen transfer due to increased local blood flow and reduces pain.2 A higher blood flow increases the delivery of nutrients and eliminates carbon dioxide, metabolic waste, and inflammatory chemical mediators. Increased local blood flow also affects the treatment efficacy of the heated target. Modulated electrohyperthermia (mEHT) is the next-generation medical innovation that delivers selective, controlled, and deep energy treatments using the capacitive-coupled energy of 13.56-MHz amplitude-modulated radiofrequency for cancer therapy.3,4 Malignant cells are selectively heated, affecting the cell membranes5 and inducing apoptosis at mild temperatures (r42°C).4,6 This treatment promotes immunogenic cell death.7,8 The mEHT does not cause pain and causes few adverse effects (AEs), resulting in improved efficacy and quality of life.9 Moreover, patients treated with mEHT have reported pain relief10 and, as a result, have used decreased doses of analgesics.11 Fentanyl is a pure opioid agonist whose principal therapeutic action is analgesia.12 Fentanyl binds to μ-opioid receptors in various locations of the central nervous system and relieves pain by increasing pain
Accepted for publication October 25, 2016. http://dx.doi.org/10.1016/j.clinthera.2016.10.012 0149-2918/$ - see front matter & 2016 Elsevier HS Journals, Inc. All rights reserved.
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S.Y. Lee and M.-G. Kim thresholds, changing pain sensations, and inhibiting ascending pain pathways.13 Fentanyl is generally considered 50 to 100 times more potent than morphine.13 The fentanyl citrate oral transmucosal lozenge* is a solid formulation of fentanyl citrate delivered on a plastic stick. Generic fentanyl citrate is a form of oral transmucosal fentanyl citrate (OTFC). The absorption pharmacokinetic properties of OTFC works via initial rapid absorption through the buccal mucosa and prolonged absorption through the gastrointestinal (GI) tract.14 The peak blood concentration is observed 20 to 40 minutes after the initiation of OTFC application.13 Thus, OTFC is used to treat breakthrough pain in patients with cancer who already received and are tolerant to around-the-clock opioid therapies for underlying persistent cancer pain.14,15 The analgesic effect of OTFC is related to the blood concentration of fentanyl at a range of 0.3 to 1.2 ng/mL, and levels in excess of 10 to 20 ng/mL are associated with surgical anesthesia and respiratory depression.16 OTFC is often consumed during mEHT therapy. The heat with radiation would be influenced by the heatinduced changes in regional blood flow.17 mEHT may affect the pharmacokinetic properties of fentanyl because of changes in the regional blood flow. The unexpected AEs can be caused by changes in the fentanyl concentration. Therefore, we examined the effects of mEHT on the pharmacokinetic properties of fentanyl in healthy volunteers.
SUBJECTS AND METHODS This study was approved by the Ministry of Food and Drug Safety and the Institutional Review Board of Chonbuk National University Hospital. This study was conducted according to the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki and according to the Good Clinical Practice guidelines. Written informed consent was obtained from each participant before screening, and a detailed explanation of the study was provided. Healthy male and female volunteers aged 19 to 55 years with body mass indexes ranging from 17.5 to 30.5 kg/m2 were enrolled in the study. The health of Trademark: ACTIQs (Cephalon, Frazer, Pennsylvania).
*
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each subject was confirmed via physical examinations, measurements of vital signs, and clinical laboratory assessments (ie, hematology, biochemistry, serology, urinalysis, and urine human chorionic gonadotropin tests for females of childbearing potential). Subjects were excluded if they had taken any prescription medications or over-the-counter drugs within 10 days before the first administration of OTFC. Subjects were also excluded if their sitting blood pressure decreased in the following ranges during the screening procedure: systolic blood pressure Z140 mm Hg and diastolic blood pressure Z90 mm Hg. Subjects were required to abstain from taking any medication without prior consent of the investigator and from drinking alcohol, smoking, and consuming food or beverages that contained caffeine during the study period. All subjects were asked to abstain from taking food or beverages that contained grapefruit for 7 days before the first administration to the discharge of the second admission. This study was conducted as an open-label, randomized-sequence, 2-period, 2-treatment, singledose, 2-way crossover trial at the Clinical Trial Center of Chonbuk National University Hospital, Jeonju, Republic of Korea. All subjects were randomly assigned to 1 of 2 treatment sequence groups: AB or BA. The 2 treatments were as follows: (A) 0.3142 mg of OTFC (Hyundai Pharmaceutical Inc, Seoul, Republic of Korea), which is equivalent to 0.2 mg of fentanyl free base and (B) 0.3142 mg of OTFC with mEHT. Each sequence group consisted of 6 subjects. Each period was followed by a 1-week washout period. On the first day of each period, all subjects were administered OTFC on day 1 at the clinical facility. OTFC was presented as a sweetened lozenge with an integral oromucosal applicator (unit) for oral administration by sucking not chewing. A unit dose of OTFC, if chewed and swallowed, might result in lower peak concentrations and lower bioavailability than when consumed as directed because the generally observed 50% bioavailability of OTFC is divided equally between rapid transmucosal and slower GI absorption. Subjects should place the OTFC unit in their mouths between the cheek and lower gum, occasionally moving the drug matrix from one side to the other using the handle. Subjects were instructed to consume the total dose within 15 minutes. All subjects received OTFC within 15 minutes. The unit was not to be bitten, chewed, or swallowed. Each
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Clinical Therapeutics mEHT treatment was applied 30 minutes after OTFC administration. Blood samples for pharmacokinetic analyses were collected before OTFC dosing (baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after OTFC dosing for a total of 13 blood samples. The blood was collected using heparinized tubes, which were temporarily stored in an icebox. For processing, the tubes were centrifuged for 10 minutes at 1811g rpm at 41C within 1 hour after sampling. One milliliter of plasma was transferred into each of 3 polypropylene tubes, and all samples were stored at 701C until further analysis. The plasma concentrations of fentanyl were analyzed using a validated LC-MS/MS method. multiple reaction monitoring (MRM) transition of m/z 337.2 - 188.1 and 452.4 - 344.4 were chosen for fentanyl and the internal standard (doxazosin). A Luna C18 (50 2.0 mm; particle size, 5 μm) analytical column was used. The mobile phase used 0.1% formic acid in water and acetonitrile. A calibration curve covering the range of 0.1 to 200 mg/mL was constructed. The calibration curves were linear over the calibration concentration range (r Z 0.9988). The intra-assay accuracy and precision were 92.7% to 108.8% and 3.0% to 12.2%, whereas the interassay accuracy and precision were 95.6% to 103.6% and 1.7% to 15.9%, respectively. Individual pharmacokinetic parameters were obtained by noncompartmental methods using Phoenix WinNonlin 6.3 software (Pharsight Corporation, Sunnyvale, California). The Cmax and Tmax were directly obtained from plasma concentration-time curves. The AUC0–last was calculated using the linear trapezoidal rule. The AUC0–1 was calculated using the equation AUC0–last þ (C0–last/ke), where AUC0–last was the area under the plasma concentration time curve to the last sampling time, C0–last was the last measurable concentration, and ke was the slope of the linear regression of the log-transformed plasma concentration time in the terminal phase. The CL/F was calculated by the equation (CL/F ¼ dose/AUC0–1), and the Vd/F was calculated by the equation (Vd/F ¼ dose/keAUC0–1). Thirty minutes after beginning OTFC administration, mEHT was applied for 60 minutes on abdomen area using an EHY2000 clinical heating device (Oncotherm GmbH, Troisdorf, Germany) with a carrier frequency of 13.56 MHz. mEHT was amplitudemodulated according to a time-fractal pattern.18
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The subjects were positioned in a supine position on a water-mattress electrode. A circular upper electrode, 30 cm in diameter, was coupled over the abdominal area covering the entire liver, both kidneys, and at least 90% of the intestines. The power output was 100 W for the first 10 minutes, 120 W for the following 10 minutes, and 150 W for the remaining treatment time. The device was calibrated before each treatment. The abdominal skin surface temperature was assessed before dosing and 10, 20, and 60 minutes after OTFC dosing. Tolerability was assessed by evaluating the physical examination findings, vital sign measurements, and laboratory test results. AEs were monitored throughout the study. AEs were determined by investigator inquiries and spontaneous patient reports. Statistical analyses were performed using SAS software, version 9.3 (SAS Institute, Cary, North Carolina). Descriptive statistics were used to summarize pharmacokinetic data. At a 5% significance level, ANOVA was used to compare pharmacokinetic parameters. The point estimates and 90% CIs of the ratios of the geometric means ratios (ratio of fentanyl with mEHT to fentanyl alone) of log-transformed Cmax and AUC0–last were compared. Because this was a descriptive study to evaluate potential drug interactions with mEHT treatment, no formal sample size estimation was performed for pharmacokinetic evaluations. Intraindividual %CVs in Cmax and AUC of fentanyl were assumed to not exceed 10%.19 A total sample size of 12 achieves an 98% power at a 5% significance level when the true ratio of the means is 1.05 and the %CV is 10%.
RESULTS Ten male and 2 female subjects (mean [SD] age, 28.9 [8.7] years; mean [SD] height, 172.6 [5.5] cm; and mean [SD] weight, 68.2 [9.0] kg) were eligible for the study and were assigned to the relevant sequence groups using a randomization process (Table I). All subjects completed the study according to the protocol. The pharmacokinetic parameters of fentanyl were evaluated and are summarized in Table II. The mean plasma concentration-time profiles are presented in Figure 1. The mean Cmax and AUC0–last of fentanyl were 0.38 ng/mL and 1.32 h ∙ ng/mL, respectively, for the fentanyl with mEHT treatment. The mean Cmax and
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S.Y. Lee and M.-G. Kim
Table I. Demographic characteristics of the 12 study subjects. Age, y
Height, cm
Weight, kg
BMI, kg/m2
28.9 (8.7) 19–51
172.5 (5.5) 158.1–180.5
68.2 (9.0) 56.5–84.4
22.9 (2.6) 19.3–26.6
Characteristic Mean (SD) Range BMI ¼ body mass index.
AUC0–last of fentanyl were 0.32 ng/mL and 1.28 h ∙ ng/mL, respectively, for the fentanyl alone treatment. The Tmax and elimination t½ values of fentanyl were similar for the 2 treatments. The point estimates of the ratios of the geometric means (ratio of test to reference) of the Cmax and AUC0–last of fentanyl administered in the fentanyl with mEHT group and fentanyl alone group were 1.20 (90% CI, 1.09–1.32) and 1.15 (90% CI, 0.99–1.33), respectively (Table III). The intrasubject %CV of the Cmax and AUC0–last of fentanyl were 13.1% and 20.6%, respectively. The ANOVA results revealed no carryover effect of any pharmacokinetic parameter. The temperature of the abdominal skin surface underneath the upper electrode before heating ranged from 36.41C to 36.91C (mean [SD], 36.51C [0.14]1C) and increased to 39.81C to 40.91C (mean [SD], 40.51C [0.36]1C). The mean surface temperature increased by approximately 41C (Figure 2).
Tolerability was assessed in 12 subjects who received the fentanyl treatments. A total of 8 AEs were reported among 5 subjects. The AEs were asthenia (3 cases) and nausea (2 cases) for the fentanyl treatment and asthenia (2 cases) and headache (1 case) for the fentanyl with mEHT treatment. All the subjects with AEs recovered within 5 hours without sequelae, and no serious AEs were observed. In addition, the results of the physical examinations, vital sign measurements, and clinical laboratory tests indicated that no clinically significant changes occurred during the study.
DISCUSSION Typically, approximately 25% of the total dose of OTFC is rapidly absorbed through the buccal mucosa and becomes systemically available.20 The absorption of OTFC is more rapid compared with other oral tablets (the pain is relieved within 15 minutes after
Table II. Pharmacokinetic parameters after a single oral administration of the 2 treatments in the 12 study subjects. Pharmacokinetic Parameter Cmax, ng/mL AUC0–last, h ∙ ng/mL AUC0–1, h ∙ ng/mL‡ Tmax, h t1/2, h‡ CL/F, L/h‡ Vd/F, L‡
Fentanyl (0.2 mg) with mEHT* 0.38 1.32 2.38 1.48 3.63 96.01 454.77
(0.09) (0.68) (0.87) (0.66) (1.42 (41.42) (198.89)
Fentanyl (0.2 mg) Alone* 0.32 1.28 2.80 1.56 5.47 87.96 598.84
(0.10) (1.13) (1.74) (0.66) (2.96) (36.46) (200.64)
P† 0.1837 0.4529 0.8480 0.7642 0.2774 0.8480 0.0845
mEHT ¼ modulated electrohyperthermia. * The values are presented as the arithmetic means (SDs). † The P values were calculated with the Wilcoxon rank-sum test. ‡ n ¼ 7; the elimination rate constant of 5 subjects cannot be calculated.
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41 Fentanyl 0.2 mg Fentanyl 0.2 mg with modulated electro hyperthermia
0.4
0.3
0.2
Fentanyal 0.2 mg Fentanyal 0.2 mg with modulated electro hyperthermia
40 Temperature (°C)
Plasma Concentration of Fentanyl (ng/mL)
0.5
39
38
0.1
37 0.0 0
6
12
18
24
36 0
Time (h)
10
20
30
40
50
60
Time (min)
Figure 1. Plasma concentration-time profiles of fentanyl after 0.3142 mg of oral transmucosal fentanyl citrate (as 0.2 mg of fentanyl) with modulated electrohyperthermia treatment and 0.3142 mg of oral transmucosal fentanyl citrate alone treatment.
administration),21 and its analgesic effect appears as rapidly as its intravenous administration.22 The remaining 75% of the total OTFC dose is slowly absorbed through the GI tract.23 Approximately onethird of this amount (ie, 25% of the total dose) escapes hepatic and intestinal first-pass elimination and becomes systemically available.22 In our study, the mean fentanyl plasma concentration-time curves displayed double peaks, which are characteristic of OTFC administration. The bioavailability of fentanyl is divided equally between rapid transmucosal absorption and slower GI absorption.14,24 Fentanyl is primarily (490%) metabolized in the liver and has a high extraction ratio,14,25–28 which makes it unlikely
Figure 2. The temperature of the abdominal skin surface after 0.3142 mg of oral transmucosal fentanyl citrate (as 0.2 mg of fentanyl) with modulated electrohyperthermia treatment and 0.3142 mg of oral transmucosal fentanyl citrate alone treatment.
to have clinically significant pharmacokinetic drug interactions during elimination.29 However, the clearance of high-extraction drugs, such as fentanyl, is affected by changes in hepatic blood flow.30 This study was designed to determine the maximum effect of slower fentanyl (GI) absorption through a 30-minute mEHT treatment beginning 60 minutes after the oral administration of OTFC. As the hyperthermia treatment progressed, the Cmax of fentanyl might be increased because of increased absorption through the digestive tract. Even after the oral dosing of fentanyl ended, the drug absorption continued to increase. Generally, orally administered drugs are
Table III. Statistical analysis of fentanyl pharmacokinetic parameters in the 12 study subjects. Geometric LS Mean Pharmacokinetic Parameter Cmax, ng/mL AUC0–last, h ∙ ng/mL
Fentanyl (0.2 mg) With mEHT
Fentanyl (0.2 mg) Alone
Geometric LS Mean Ratio (90% CI)
0.37 1.18
0.31 1.03
1.20 (1.09–1.32) 1.15 (0.99–1.33)
LS ¼ least squares; mEHT ¼ modulated electrohyperthermia.
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S.Y. Lee and M.-G. Kim absorbed through the GI tract via the blood supply. mEHT treatments increase the temperature of the targeted region, inducing increased blood flow.11 Thus, abdominal mEHT induces increased blood flow in the abdominal region and affects the pharmacokinetic properties of orally administered drugs.31 Our results reveal that slightly increased Cmax indicated an increased drug absorption rate by mEHT. However, considering that the increase in Cmax was not significant, these findings are not expected to influence the expected therapeutic effect of fentanyl. The changes in the AUC did not affect the metabolism or the excretion of the drug during hyperthermia, and hyperthermia might not affect the overall therapeutic efficacy of fentanyl. This study has some limitations. The study was conducted only on heathy subjects. Intestinal or hepatic blood flow also remains to be measured during the hyperthermia treatment progress. Therefore, additional studies in patients with cancer might be beneficial for evaluating the pharmacokinetic properties of fentanyl and measuring intestinal or haptic blood flow.
CONCLUSIONS In conclusion, few differences were observed in the overall disposition of the drug; thus, the combination of fentanyl and mEHT treatment may not have had any clinical significance. Therefore, OTFC can be administered with or without mEHT, and a modification of the dosing regimen is unnecessary.
ACKNOWLEDGMENTS Sun Young Lee contributed to the data collection as a principal investigator and wrote the manuscript. MinGul Kim contributed to the data collection as a coinvestigator, participated in the data analyses, and wrote and reviewed the manuscript.
FUNDING SOURCES This study was supported by Hyundai Pharmaceutical, Inc., Seoul, Republic of Korea.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Address correspondence to: Min-Gul Kim, MD, PhD, Department of Pharmacology, Chonbuk National University Medical School, Jeonju, Jeonbuk, Republic of Korea. E-mail: [email protected]
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