- Email: [email protected]
Single-dose, Randomized, Open-label, 2-way Crossover Study of the Pharmacokinetics of Amitriptyline Hydrochloride 10- and 25-mg Tablet in Healthy Male Korean Volunteers
Clinical Therapeutics/Volume ], Number ], 2014
Single-Dose, Randomized, Open-Label, 2-Way Crossover Study of the Pharmacokinetics of Amitriptyline Hydrochloride 10- and 25-mg Tablet in Healthy Male Korean Volunteers Yunsung Nam, PhD1; Cheol-Hee Lim, PhD1; Ho Sung Lee, MS1; Su Jin Chung, BS1; Yoon Hee Chung, PhD2; Yong Kyoo Shin, MD, PhD1; Min-Gul Kim, MD, PhD3; Uy Dong Sohn, PhD4; Hyoung-Chun Kim, PhD5; and Ji Hoon Jeong, PhD1 1
Department of Pharmacology, College of Medicine, Chung-ang University, Seoul, Republic of Korea; Department of Anatomy, College of Medicine, Chung-ang University, Seoul, Republic of Korea; 3 Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; 4 Department of pharmacology, College of Pharmacy, Chung-ang University, Seoul, Republic of Korea; and 5 Neuropsychopharmacology & Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea 2
ABSTRACT Purpose: Amitriptyline is the most widely used tricyclic antidepressant (TCA). Although amitriptyline hydrochloride 10 and 25 mg has been marketed in Korea, no data on the dose proportionality of amitriptyline in Korean subjects are available. This clinical trial was designed to evaluate and compare the relative bioavailability with regard to dose proportionality between the two marketed strengths of amitriptyline hydrochloride tablets after a single-dose, oral administration under fasting conditions in healthy, male, Korean volunteers. Methods: This single-dose, randomized, open-label, 2-way crossover study was conducted in healthy male Korean subjects. Subjects were randomly assigned to 1 of 2 dose groups and received a single dose of 10 or 25 mg amitriptyline hydrochloride under fasting conditions, followed by the alternate dose in the subsequent study period. High performance liquid chromatography (HPLC)- mass spectrometry (MS)/ MS detection was applied to determine plasma concentrations. Pharmacokinetic parameters were calculated, Cmax, AUClast, AUC0–1, t½, and Tmax. Statistical analysis was performed for the assessment of dose proportionality. Tolerability was assessed for up to 96 hours after administration. Findings: Twelve healthy Korean subjects completed this trial (mean [SD] age, 21.7 [1.9] years; height, 174.5 [5.0] cm; and weight, 66.7 [9.4] kg). Although 4 subjects experienced a total 5 adverse events (AEs),
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no serious AEs were reported during the study. The mean values of Cmax and AUC were proportional to the doses of 10 and 25 mg. The Cmax, AUClast, and AUC0–1 of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng h/mL and 109.74 ng h/mL, respectively. The Cmax, AUClast, and AUC0–1 of amitriptyline hydrochloride 25 mg were 17.69 ng/mL, 260.68 ng h/mL, and 296.87 ng h/mL, respectively. Implications: Our results suggest that the 2 strengths of amitriptyline hydrochloride (10 and 25 mg) exhibited linear (dose-dependent) pharmacokinetics in these healthy, male, Korean subjects. Based on these results, a predictable and linear increase in systemic exposure can be expected.ClinicalTrials.gov identifier: NCT01367080. (Clin Ther. 2014;]:]]]–]]]) & 2014 Published by Elsevier HS Journals, Inc. Keywords: amitriptyline hydrochloride, antidepressant, Etravil, pharmacokinetic, proportionality.
INTRODUCTION Amitriptyline was developed by Merck & Co, Inc, and was approved by the US Food and Drug Administration on April 7, 1961, for the treatment of major depression.1 Amitriptyline is the most widely used Accepted for publication September 6, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.09.010 0149-2918/$ - see front matter & 2014 Published by Elsevier HS Journals, Inc.
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Clinical Therapeutics tricyclic antidepressant (TCA). In Korea, amitriptyline hydrochloride 10 and 25 mg are commercially available.*† Although TCAs have largely been replaced in recent decades by new classes of antidepressants such as serotonin–norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, amitriptyline is still frequently used.2 Amitriptyline has a wide range of pharmacologic actions. In addition to increasing receptor-site concentrations of norepinephrine and serotonin,3,4 amitriptyline has an affinity for the muscarinic, histaminergic, cholinergic, and adrenergic systems.5,6 Amitriptyline has been suggested to interact with the σ-1 receptor,7 tropomyosin receptor kinase receptor,8 N-methyl-D-aspartate receptor, and phencyclidine receptor.9 Amitriptyline is also a sodium, calcium, and potassium channel blocker.10,11 Amitriptyline offers variability in dosing, often ranging between 25 and 150 mg. The drug has been associated with a number of adverse events (AEs) such as blurred vision, constipation, urination problems, dry mouth, delirium, vertigo, and sedation.2 Although many studies have been conducted with regard to treating amitriptyline overdose and acute poisoning,12,13 few data on the dose proportionality of amitriptyline in Korean subjects are available. Thus, this study was designed to evaluate and compare relative bioavailability in terms of dose proportionality between the 2 marketed strengths (10 and 25 mg) of amitriptyline hydrochloride tablets after single-dose, oral administration in fasting, healthy, male, Korean volunteers.
SUBJECTS AND METHODS Study Design In this single-dose, single-center, randomized, openlabel, 2-way crossover study, a single oral dose of amitriptyline hydrochloride 10 or 25 mg was administered under fasting conditions in each study period. To ensure that no carryover effect was observed, a washout period of 14 calendar days was instituted between drug administrations, corresponding to 410fold the expected half-life of the moiety to be measured. The randomization code was not made available Marketed as Endeps (Roche), Etravils (DDSA), Laroxyls (Roche), Lentizols (Parke-Davis), Sarotexs (H. Lundbeck), and Tryptizols (Merck Sharp & Dohme). † Trademark: Etravils (Dong-Hwa Pharmaceutical Corporation, Seoul, Korea). *
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to the personnel in charge of the determination of plasma drug concentrations until the results were audited by the quality-assurance department. The protocol and informed-consent forms were approved by the institutional review board of the Chung-ang University College of Medicine (Seoul, Korea). All subjects voluntarily agreed to participate in this study and provided informed consent before the initiation of the study procedures. This study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guideline for Good Clinical Practice.14,15
Study Population Healthy, male, Korean volunteers between 19 and 50 years of age were enrolled in this trial. Volunteerscreening procedures included informed consent; inclusion/exclusion criteria assessment; collection of demographic data, medical history, medication history, and physical-examination data; and ECG and laboratory test results (routine blood chemistry, blood cell count with white blood cell differential, urinalyses, and coagulation tests). Eligible participants’ weights were 450 kg and within 20% of the ideal body weight for height.16 Subjects were excluded if they had congenital or chronic disease, a history of clinically significant diseases or drug hypersensitivity, use of prescription medication within 14 days or over-the-counter medications within 7 days before dosing, low or high blood pressure (systolic blood pressure, r100 or Z150 mm Hg, diastolic blood pressure, r65 or Z95 mm Hg), blood donation o60 days before dosing, excessive alcohol or caffeine consumption, and/or smoking habit. All participating subjects were considered eligible for the study after the assessment of the inclusion and exclusion criteria. Participants were immediately removed from the study if safety issues arose as determined by the investigator. They could also be withdrawn because of protocol violations, administrative problems, and difficulties in blood collection, emesis during the time interval described in the protocol, and/or other reasons described in the protocol. Furthermore, subjects were allowed to discontinue their participation in the study at any time.
Treatment Schedule Subjects received the amitriptyline hydrochloride tablet 10 or 25 mg in the first study period under Volume ] Number ]
Y. Nam et al. fasting conditions according to the randomization list. Food was controlled and standardized during the housing period. Subjects fasted overnight for at least 10 hours before drug administration. A single dose of amitriptyline hydrochloride was thereafter administered orally with approximately 240 mL of water at ambient temperature. Participants were instructed to swallow the amitriptyline hydrochloride tablet whole and not to chew or break it. Fasting continued for at least 4 hours after drug administration, and water was allowed ad libitum beginning 2 hours from drug administration. Standardized lunch and dinner were served 4 and 9 hours after drug administration, respectively. After 14-day washout, the alternate dose was administered using the same protocol.
Blood Sampling and Analysis Blood samples were collected in tubes containing K2EDTA at 0 (predose), 0.5, 1, 2, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after drug administration. This sampling scheme was planned to provide a reliable estimate of the extent of absorption and the terminal elimination half-life, as well as to ensure that the AUClast value was at least 80% of the AUC0–1 value. Blood was obtained from an inserted heparinlock catheter. Plasma was extracted by centrifugation at 1800g for 8 minutes at 41C and immediately transferred to a 1.5-mL Eppendorf tube. Plasma samples were stored at –7010 until assay. The experimental samples were assayed for amitriptyline, using a validated HPLC-MS/MS method. The mobile phase consisted of 85:15 (vol/vol) acetonitrile and 0.5% formic acid in distilled water. A volume of 5 μL was injected into a Luna C8 column (2.0 150 mm, 3-μm internal diameter; Phenomenex, Inc, Torrance, California), and the transitions (m/z) for both amitriptyline (278.1/233.3) and an internal standard (clopidogrel, 322.1/212.1) were monitored using multiple reaction monitoring ion mode.
sign measurements were performed at regular intervals.
Statistical Analysis Based on findings from a previous study, the intrasubject variability of AUCt for this product is 21.0%.17 Assuming the expected geometric mean ratio (GMR) of dose-normalized AUCt was within the bioequivalence range of 80% to 125% with a statistical power of at least 90% to detect a significant difference (α ¼ 0.05) in between-dose 90% CI, it was estimated that the minimum number of subjects required was 6. To exclude the influence of various factors, pharmacokinetic (PK) properties were studied in healthy male individuals, using the same medicinal products, methods of quantitative determination of drug plasma concentration, and calculations of PK parameters. The demographic characteristics of the study subjects were summarized and assessed using descriptive statistics, the Wilcoxon rank-sum test, or the Fisher exact test. The numbers of subjects experiencing AEs were compared between doses using the Fisher exact test or the Kruskal-Wallis test, and P values o0.05 were considered statistically significant. All PK parameters were summarized using descriptive statistics. Statistical comparison was performed using ANOVA, with a linear mixed-effects model. The fixed effects included in this model were the subject effect, the dose received, the period in which each dose was given, as well as the sequence in which the 2 doses were received. Proportionality was assumed if the 90% CI of the dose-normalized GMR of AUCt was within the 80.0% to 125.0% range. Analysis of the PK data was performed using WinNonlin version 5.3 (Pharsight Corporation, Mountain View, California). Statistical evaluation was conducted using SPSS Statistics version 20 (IBM SPSS Statistics, IBM Corporation, Armonk, New York).
Tolerability Assessments Tolerability was evaluated through the assessment of AEs, standard laboratory evaluations, and vital signs. The regular monitoring and recording of all AEs included any symptoms, their time of onset and resolution, duration, severity, and relationship to the study drug. Routine blood chemistry analysis, blood cell counts with white blood cell differential, urinalyses, physical examinations, ECGs, and vital
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RESULTS Subject Characteristics As shown in Figure 1, a total of 15 healthy, male, Korean volunteers participated in this study, and 12 subjects completed the crossover phase and received a single oral dose of the assigned treatment on days 1 and 15. Three volunteers dropped out of this trial (laboratory abnormality [n ¼ 1], withdrawal of
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N = 15 Volunteer screened N=3 Screening failures Reasons: Lab. abnormality (1) Consent withdrawn (1) ineligible (1)
N = 12 Subjects randomized
N=6 Group 1 - amitriptyline hydrochloride 10 mg
N=6 Group 2 - amitriptyline hydrochloride 25 mg
2 wk washout
2 wk washout
N=6 Group 1 - amitriptyline hydrochloride 25 mg
N=6 Group 2 - amitriptyline hydrochloride 10 mg
N = 12 Completed
Figure 1. Flow diagram of this study of single-dose, oral administration of amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects.
Table I. Baseline demographic and clinical characteristics in this study of amitriptyline hydrochloride in healthy, male, Korean subjects. Characteristic Age, y Height, cm Weight, kg Substance intake Alcohol (yes/no) Smoking (nicotine) (yes/no) Caffeine (yes/no)
Group 1* (n ¼ 6)
Group 2† (n ¼ 6)
All Patients (N ¼ 12)
P
22.2 (1.7) 176.0 (5.3) 70.2 (12.6)
21.2 (2.1) 173.0 (4.6) 63.2 (2.6)
21.7 (1.9) 174.5 (5.0) 66.7 (9.4)
0.323‡ 0.421‡ 0.200‡
4/2 0/6 5/1
3/3 0/6 2/4
7/5 0/12 7/5
1.0§ 1.0§ 0.242§
*
Received amitriptyline hydrochloride 10 mg in study period 1 and 25 mg in study period 2. Received amitriptyline hydrochloride 25 mg in study period 1 and 10 mg in study period 2. ‡ Wilcoxon rank sum test. § Fisher exact test. †
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Y. Nam et al. consent [n ¼ 1], and lack of eligibility [n ¼ 1]). The baseline characteristics of the 12 subjects are listed in Table I. Their mean (SD) age, height, and weight were 21.7 (1.9) years, 174.5 (5.0) cm, and 66.7 (9.4) kg, respectively.
Tolerability All of the subjects received the amitriptyline hydrochloride tablets according to the protocol, under supervision of Min-Gul Kim. Amitriptyline hydrochloride was well tolerated when administered orally at doses of 10 and 25 mg, and no serious AEs were reported during this study. As summarized in Table II, a total of 5 AEs occurred in 4 subjects. After the administration of amitriptyline hydrochloride 10 mg, 2 subjects reported 3 AEs; after the administration of amitriptyline hydrochloride 25 mg, 2 subjects reported 2 AEs. It was determined that drug administration may have had a causal relationship with the 4 reported events (dizziness [2 subjects in the 10-mg group] and asthenia [1 subject each in the 10- and 25-mg groups]). All of the AEs were rated as mild, and all subjects recovered without intervention.
Pharmacokinetic Properties and Statistical Analysis The mean plasma concentration–time profiles after a single oral dose of the study drug are shown in Figure 2.
The PK parameters are summarized in Table III. Dose proportionality between the 2 strengths (10 and 25 mg) of amitriptyline hydrochloride was observed in the mean values of Cmax and AUC. The Cmax, AUClast, and AUC0–1 values of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng h/mL, and 109.74 ng h/mL, respectively. The Cmax, AUClast, and AUC0–1 of amitriptyline 25 mg were 17.69 ng/mL, 260.68 ng h/mL, and 296.87 ng h/mL. As shown in Figure 3 and Table IV, linear regression analysis revealed significant linearity in Cmax, AUClast, and AUC0–1. In addition, we determined that the point estimate values of the dose-normalized GMRs of Cmax, AUClast, and AUC0–1 were within the predetermined 90% CI range for relative bioavailability with regard to dose proportionality (Table V).
DISCUSSION There have been few reports on the dose proportionality of the PK properties of amitriptyline hydrochloride in healthy Korean subjects. This clinical study was designed to evaluate and compare relative bioavailability with regard to dose proportionality between the 2 marketed strengths (10 and 25 mg) of amitriptyline hydrochloride tablets after single-dose administration in fasting, healthy, male, Korean subjects. Amitriptyline is readily absorbed in the gastrointestinal tract and is metabolized in the liver.18 It is
Table II. Adverse events reported with single-dose administration of amitriptyline hydrochloride 10 or 25 mg tablets in healthy, male, Korean subjects.* Parameter No. of subjects No. of AEs Nerve system disorders Dizziness General disorders and administration site condition Asthenia
10 mg (n ¼ 6)
25 mg (n ¼ 6)
All Patients (N ¼ 12)
P
2 3
2 2
4 5
1.0† 0.929‡
2§
1
—
—
1§
1§
—
—
*
None of the AEs were considered serious by the investigator; all AEs were rated as mild. Fisher’s exact test. ‡ Kruskal-Wallis test. § Considered by the investigator possibly treatment related. †
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25
Plasma Concentration (ng/mL)
20
10 mg 25 mg
15
10
5
0 0 2 4 6 8 1012
24
36 Time (h)
48
72
Figure 2. Mean (SD) plasma drug concentration–time curves after single-dose, oral administration of amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects.
Table III. Pharmacokinetic properties of single-dose amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects. Property Cmax Mean (SD), ng/mL Cmax/D, mean (SD), ng/mL %CV AUClast Mean (SD), ng h/mL AUClast/D, mean (SD), ng h/mL %CV AUC0–1 Mean (SD), ng h/mL AUC0–1, mean (SD), ng h/mL %CV t½, h Mean (SD) %CV Tmax, h* Mean (SD) Median (range) %CV
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10 mg (n ¼ 6)
25 mg (n ¼ 6)
5.96 (1.40) 0.60 (0.14) 23.41
17.69 (5.27) 0.71 (0.21) 29.81
91.35 (25.88) 9.14 (2.59) 28.33
260.68 (111.57) 10.43 (4.46) 42.80
109.74 (37.80) 10.97 34.44
296.87 (124.99) 11.87 (5.00) 42.10
26.47 (5.64) 21.29
24.79 (3.22) 12.98
3.50 (0.90) 3.50 (2.0–6.0) 25.84
3.31 (0.61) 3.25 (2.0–4.0) 19.45
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Y. Nam et al.
30 25
Cmax (ng/mL)
B
Dose vs Cmax Regression line 95% CI
600
Dose vs AUClast Regression line 95% CI
500 AUClast (ng.h/mL)
A
20 15 10
400 300 200 100
5 0
10
0
25
10
Dose (mg)
C
600
AUC0– (ng.h/mL)
500
25 Dose (mg)
Dose vs AUC0– Regression line 95% CI
400 300 200 100 0
10
25 Dose (mg)
Figure 3. Linear regression profile of dose-Cmax (A), dose-AUClast (B) and dose-AUC0–1 (C) after single-dose, oral administration of amitriptyline hydrochloride 10 or 25 mg in healthy, male, Korean subjects.
widely distributed throughout the body and excreted in the urine.19 The absorption, distribution, metabolism, and excretion process of this drug may be affected by a variety of factors, and the fact that this trial adhered to a single-dose, openlabel design and was performed in these selected healthy Korean subjects under carefully controlled conditions should be taken into account when interpreting the results.
In this study, amitriptyline hydrochloride was well tolerated. Although some subjects experienced AEs, none were serious. The lack of serious AEs may have been due to the low doses of amitriptyline hydrochloride administered in this study. A single dose of 10 or 25 mg is lower than the typical dose of 150 mg/d. It has been shown previously that a low dosage of amitriptyline (75 mg/d) was associated with fewer AEs than was a higher dose (150 mg/d).20,21 Dose
Table IV. Linear regression analysis of single-dose administration of 10 and 25 mg amitriptyline hydrochloride in healthy, male, Korean subjects. Slope Parameter Cmax AUClast AUC0–1
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y-Intercept
Value
95% CI
P
Value
95% CI
P
0.782 11.288 12.475
0.546 to 0999 6.717 to 15.860 7.234 to 17.687
o0.001 o0.001 o0.001
–1.855 –21.529 –15.012
–6.000 to 2.288 –108.565 to 65.507 –114.240 to 84.272
0.363 0.613 0.757
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Table V. ANOVA regression model of single-dose amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects. Parameter Cmax AUClast AUC0–1
GMR
90% CI
1.1621 1.1002 1.0585
1.0554–1.2796 0.9952–1.2163 0.9369–1.1960
GMR ¼ geometric mean ratio.
proportionality between the 2 strengths (10 and 25 mg) of amitriptyline hydrochloride was observed in the mean values of Cmax and AUC, indicating that the 2 strengths amitriptyline hydrochloride (10 and 25 mg) have linear PK properties, and that 10 and 25 mg of amitriptyline hydrochloride were dose proportional in these healthy, male, Korean subjects. Although only 2 strengths were tested, our results suggest that systemic exposure to amitriptyline hydrochloride of increasing strengths will yield a predictable and linear increase in plasma drug concentration. In a previous study, the linearity of the kinetics of twice-daily amitriptyline were tested in 135 depressed patients, by measuring plasma concentrations.22 Although there was a linear relationship between the dose ratios and the concentration ratios, there may have been nonlinear kinetics in some patients, as the ratio between the concentration/dose ratios at low and high dosages was 41. An investigation of the disposition of amitriptyline after the administration of a single dose, as well as after long-term administration, suggested that there have been some of the discrepancies in the mean values of the PK parameters of amitriptyline.23 Broad individual variability in the elimination rate of amitriptyline has also been confirmed.23 The significant interindividual differences in amitriptyline PK properties in humans have been associated with genetic polymorphisms in the cytochrome (CYP) 2D6 isozyme. CYP2D6 has a key role in the metabolism of TCAs.24 It is well known that CYP2D6 activity is limited in 7% of the white population and in 1% to 3% of other ethnic groups.25 The results obtained in studies in healthy Korean subjects serve as a key point for the evaluation of the
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efficacy and tolerability of medical products in clinical use. However, the extrapolation of the data obtained in this clinical trial may limit the generalizability of our findings in the general population because of the complexities of the inclusion/exclusion criteria, dietary restrictions in the study protocol, and ethnic differences between the Korean and general populations.
CONCLUSIONS The exposure to amitriptyline hydrochloride was proportional over the low-dose therapeutic range of 10 to 25 mg in these healthy, male, Korean subjects, with a dose-proportional increase in the overall exposure to amitriptyline hydrochloride and the Cmax achieved. Tmax values in plasma were similar between the 10- and 25-mg doses. Based on these findings, a predictable and linear increase in systemic exposure can be expected in the tested doses of amitriptyline. Amitriptyline hydrochloride was well tolerated in these healthy, male, Korean volunteers.
ACKNOWLEDGMENTS The study was conducted at the Clinical Trial Center at Chonbuk National University Hospital. The sponsor monitored the study but had no role in conducting the study procedures, data analyses, or interpretation. Drs. Nam and Lim contributed equally to this work. Dr. Lim was the principal investigator of the trial. Drs. S.J. Chung, Y.H. Chung, Shin, Min-Gul Kim, and Sohn equally contributed to the study design and to the data analyses. Dr. Nam and Lee contributed to the review of the data analyses, literature search, figure/table creation, and manuscript writing. Dr. Hyoung-Chun Kim helped to revise the manuscript. Prof. Jeong made the final decision regarding manuscript submission.
CONFLICTS OF INTEREST This study was funded by Dong-Hwa Pharmaceutical Corporation (Seoul, Korea), manufacturers of amitriptyline hydrochloride. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
REFERENCES 1. Fangmann P, Assion HJ, Juckel G, et al. Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics.
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Part II: tricyclics and tetracyclics. J Clin Psychopharmacol. 2008;28:1–4. Leucht C, Huhn M, Leucht S. Amitriptyline versus placebo for major depressive disorder. Cochrane Database Syst Rev. 2012:12. (CD009138). Tatsumi M, Groshan K, Blakely RD, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997; 340:249–258. Garattini S. The need to compare the effectiveness of the available antidepressant drugs. Br J Psychiatry. 1988;152:140–141. Dilsaver SC, Snider RM, Alessi NE. Amitriptyline supersensitizes a central cholinergic mechanism. Biol Psychiatry. 1987;22:495–507. Nguyen T, Shapiro DA, George SR, et al. Discovery of a novel member of the histamine receptor family. Mol Pharmacol. 2001;59:427–433. Werling LL, Keller A, Frank JG, et al. A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol. 2007; 207:248–257. Jang SW, Liu X, Chan CB, et al. Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity. Chem Biol. 2009;16:644–656. Sills MA, Loo PS. Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate. Mol Pharmacol. 1989; 36:160–165. Pancrazio JJ, Kamatchi GL, Roscoe AK, et al. Inhibition of neuronal Naþ channels by antidepressant drugs. J Pharmacol Exp Ther. 1998;284: 208–214. Punke MA, Friederich P. Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels. Anesth Analg. 2007;104:1256–1264, tables of contents.
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12. Paksu S, Duran L, Altuntas M, et al. Amitriptyline overdose in emergency department of university hospital: Evaluation of 250 patients. Hum Exp Toxicol. 2014;33:980–990. 13. Karaci M, Ozcetin M, Dilsiz G, et al. Severe childhood amitriptyline intoxication and plasmapheresis: a case report. Turk J Pediatr. 2013;55:645–647. 14. ICH harmonized tripartite guideline: Guideline for Good Clinical Practice. J Postgrad Med. 2001;47:45–50. 15. [The Helsinki Declaration]. Assist Inferm Ric. 2010;29:41–44. 16. Pai MP, Paloucek. FP. The origin of the “ideal” body weight equations. Ann Pharmacother. 2000;34:1066– 1069. 17. Kukes VG, Kondratenko SN, Savelyeva MI, et al. Experimental and clinical pharmacokinetics of amitryptiline: comparative analysis. Bull Exp Biol Med. 2009;147:434–437. 18. Shen Y, Zhu RH, Li HD, et al. Validated LC-MS (ESI) assay for the simultaneous determination of amitriptyline and its metabolite nortriptyline in rat plasma: application to a pharmacokinetic comparison. J Pharm Biomed Anal. 2010;53:735– 739. 19. Hucker HB, Balletto AJ, Demetriades J, et al. Urinary metabolites of
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amitriptyline in the dog. Drug Metab Dispos. 1977;5:132–142. Miljkovic B, Pokrajac M, Timotijevic I, et al. Clinical response and plasma concentrations of amitriptyline and its metabolite-nortriptyline in depressive patients. Eur J Drug Metab Pharmacokinet. 1996;21:251– 255. Vezmar S, Miljkovic B, Vucicevic K, et al. Pharmacokinetics and efficacy of fluvoxamine and amitriptyline in depression. J Pharmacol Sci. 2009; 110:98–104. Vandel S, Bertschy G, Vandel B, et al. Amitriptyline: linear or nonlinear kinetics in every day practice? Eur J Clin Pharmacol. 1989;37:595– 598. Schulz P, Dick P, Blaschke TF, et al. Discrepancies between pharmacokinetic studies of amitriptyline. Clin Pharmacokinet. 1985;10:257–268. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151:737–748. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005;5: 6–13.
Address correspondence to: Ji Hoon Jeong, PhD, Department of pharmacology, College of medicine, Chung-ang University, Heuk-seok 156-756, Dong-jak gu, Seoul, Republic of Korea. E-mail: [email protected]
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Single-Dose, Randomized, Open-Label, 2-Way Crossover Study of the Pharmacokinetics of Amitriptyline Hydrochloride 10- and 25-mg Tablet in Healthy Male Korean Volunteers Yunsung Nam, PhD1; Cheol-Hee Lim, PhD1; Ho Sung Lee, MS1; Su Jin Chung, BS1; Yoon Hee Chung, PhD2; Yong Kyoo Shin, MD, PhD1; Min-Gul Kim, MD, PhD3; Uy Dong Sohn, PhD4; Hyoung-Chun Kim, PhD5; and Ji Hoon Jeong, PhD1 1
Department of Pharmacology, College of Medicine, Chung-ang University, Seoul, Republic of Korea; Department of Anatomy, College of Medicine, Chung-ang University, Seoul, Republic of Korea; 3 Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Republic of Korea; 4 Department of pharmacology, College of Pharmacy, Chung-ang University, Seoul, Republic of Korea; and 5 Neuropsychopharmacology & Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea 2
ABSTRACT Purpose: Amitriptyline is the most widely used tricyclic antidepressant (TCA). Although amitriptyline hydrochloride 10 and 25 mg has been marketed in Korea, no data on the dose proportionality of amitriptyline in Korean subjects are available. This clinical trial was designed to evaluate and compare the relative bioavailability with regard to dose proportionality between the two marketed strengths of amitriptyline hydrochloride tablets after a single-dose, oral administration under fasting conditions in healthy, male, Korean volunteers. Methods: This single-dose, randomized, open-label, 2-way crossover study was conducted in healthy male Korean subjects. Subjects were randomly assigned to 1 of 2 dose groups and received a single dose of 10 or 25 mg amitriptyline hydrochloride under fasting conditions, followed by the alternate dose in the subsequent study period. High performance liquid chromatography (HPLC)- mass spectrometry (MS)/ MS detection was applied to determine plasma concentrations. Pharmacokinetic parameters were calculated, Cmax, AUClast, AUC0–1, t½, and Tmax. Statistical analysis was performed for the assessment of dose proportionality. Tolerability was assessed for up to 96 hours after administration. Findings: Twelve healthy Korean subjects completed this trial (mean [SD] age, 21.7 [1.9] years; height, 174.5 [5.0] cm; and weight, 66.7 [9.4] kg). Although 4 subjects experienced a total 5 adverse events (AEs),
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no serious AEs were reported during the study. The mean values of Cmax and AUC were proportional to the doses of 10 and 25 mg. The Cmax, AUClast, and AUC0–1 of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng h/mL and 109.74 ng h/mL, respectively. The Cmax, AUClast, and AUC0–1 of amitriptyline hydrochloride 25 mg were 17.69 ng/mL, 260.68 ng h/mL, and 296.87 ng h/mL, respectively. Implications: Our results suggest that the 2 strengths of amitriptyline hydrochloride (10 and 25 mg) exhibited linear (dose-dependent) pharmacokinetics in these healthy, male, Korean subjects. Based on these results, a predictable and linear increase in systemic exposure can be expected.ClinicalTrials.gov identifier: NCT01367080. (Clin Ther. 2014;]:]]]–]]]) & 2014 Published by Elsevier HS Journals, Inc. Keywords: amitriptyline hydrochloride, antidepressant, Etravil, pharmacokinetic, proportionality.
INTRODUCTION Amitriptyline was developed by Merck & Co, Inc, and was approved by the US Food and Drug Administration on April 7, 1961, for the treatment of major depression.1 Amitriptyline is the most widely used Accepted for publication September 6, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.09.010 0149-2918/$ - see front matter & 2014 Published by Elsevier HS Journals, Inc.
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Clinical Therapeutics tricyclic antidepressant (TCA). In Korea, amitriptyline hydrochloride 10 and 25 mg are commercially available.*† Although TCAs have largely been replaced in recent decades by new classes of antidepressants such as serotonin–norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, amitriptyline is still frequently used.2 Amitriptyline has a wide range of pharmacologic actions. In addition to increasing receptor-site concentrations of norepinephrine and serotonin,3,4 amitriptyline has an affinity for the muscarinic, histaminergic, cholinergic, and adrenergic systems.5,6 Amitriptyline has been suggested to interact with the σ-1 receptor,7 tropomyosin receptor kinase receptor,8 N-methyl-D-aspartate receptor, and phencyclidine receptor.9 Amitriptyline is also a sodium, calcium, and potassium channel blocker.10,11 Amitriptyline offers variability in dosing, often ranging between 25 and 150 mg. The drug has been associated with a number of adverse events (AEs) such as blurred vision, constipation, urination problems, dry mouth, delirium, vertigo, and sedation.2 Although many studies have been conducted with regard to treating amitriptyline overdose and acute poisoning,12,13 few data on the dose proportionality of amitriptyline in Korean subjects are available. Thus, this study was designed to evaluate and compare relative bioavailability in terms of dose proportionality between the 2 marketed strengths (10 and 25 mg) of amitriptyline hydrochloride tablets after single-dose, oral administration in fasting, healthy, male, Korean volunteers.
SUBJECTS AND METHODS Study Design In this single-dose, single-center, randomized, openlabel, 2-way crossover study, a single oral dose of amitriptyline hydrochloride 10 or 25 mg was administered under fasting conditions in each study period. To ensure that no carryover effect was observed, a washout period of 14 calendar days was instituted between drug administrations, corresponding to 410fold the expected half-life of the moiety to be measured. The randomization code was not made available Marketed as Endeps (Roche), Etravils (DDSA), Laroxyls (Roche), Lentizols (Parke-Davis), Sarotexs (H. Lundbeck), and Tryptizols (Merck Sharp & Dohme). † Trademark: Etravils (Dong-Hwa Pharmaceutical Corporation, Seoul, Korea). *
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to the personnel in charge of the determination of plasma drug concentrations until the results were audited by the quality-assurance department. The protocol and informed-consent forms were approved by the institutional review board of the Chung-ang University College of Medicine (Seoul, Korea). All subjects voluntarily agreed to participate in this study and provided informed consent before the initiation of the study procedures. This study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guideline for Good Clinical Practice.14,15
Study Population Healthy, male, Korean volunteers between 19 and 50 years of age were enrolled in this trial. Volunteerscreening procedures included informed consent; inclusion/exclusion criteria assessment; collection of demographic data, medical history, medication history, and physical-examination data; and ECG and laboratory test results (routine blood chemistry, blood cell count with white blood cell differential, urinalyses, and coagulation tests). Eligible participants’ weights were 450 kg and within 20% of the ideal body weight for height.16 Subjects were excluded if they had congenital or chronic disease, a history of clinically significant diseases or drug hypersensitivity, use of prescription medication within 14 days or over-the-counter medications within 7 days before dosing, low or high blood pressure (systolic blood pressure, r100 or Z150 mm Hg, diastolic blood pressure, r65 or Z95 mm Hg), blood donation o60 days before dosing, excessive alcohol or caffeine consumption, and/or smoking habit. All participating subjects were considered eligible for the study after the assessment of the inclusion and exclusion criteria. Participants were immediately removed from the study if safety issues arose as determined by the investigator. They could also be withdrawn because of protocol violations, administrative problems, and difficulties in blood collection, emesis during the time interval described in the protocol, and/or other reasons described in the protocol. Furthermore, subjects were allowed to discontinue their participation in the study at any time.
Treatment Schedule Subjects received the amitriptyline hydrochloride tablet 10 or 25 mg in the first study period under Volume ] Number ]
Y. Nam et al. fasting conditions according to the randomization list. Food was controlled and standardized during the housing period. Subjects fasted overnight for at least 10 hours before drug administration. A single dose of amitriptyline hydrochloride was thereafter administered orally with approximately 240 mL of water at ambient temperature. Participants were instructed to swallow the amitriptyline hydrochloride tablet whole and not to chew or break it. Fasting continued for at least 4 hours after drug administration, and water was allowed ad libitum beginning 2 hours from drug administration. Standardized lunch and dinner were served 4 and 9 hours after drug administration, respectively. After 14-day washout, the alternate dose was administered using the same protocol.
Blood Sampling and Analysis Blood samples were collected in tubes containing K2EDTA at 0 (predose), 0.5, 1, 2, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours after drug administration. This sampling scheme was planned to provide a reliable estimate of the extent of absorption and the terminal elimination half-life, as well as to ensure that the AUClast value was at least 80% of the AUC0–1 value. Blood was obtained from an inserted heparinlock catheter. Plasma was extracted by centrifugation at 1800g for 8 minutes at 41C and immediately transferred to a 1.5-mL Eppendorf tube. Plasma samples were stored at –7010 until assay. The experimental samples were assayed for amitriptyline, using a validated HPLC-MS/MS method. The mobile phase consisted of 85:15 (vol/vol) acetonitrile and 0.5% formic acid in distilled water. A volume of 5 μL was injected into a Luna C8 column (2.0 150 mm, 3-μm internal diameter; Phenomenex, Inc, Torrance, California), and the transitions (m/z) for both amitriptyline (278.1/233.3) and an internal standard (clopidogrel, 322.1/212.1) were monitored using multiple reaction monitoring ion mode.
sign measurements were performed at regular intervals.
Statistical Analysis Based on findings from a previous study, the intrasubject variability of AUCt for this product is 21.0%.17 Assuming the expected geometric mean ratio (GMR) of dose-normalized AUCt was within the bioequivalence range of 80% to 125% with a statistical power of at least 90% to detect a significant difference (α ¼ 0.05) in between-dose 90% CI, it was estimated that the minimum number of subjects required was 6. To exclude the influence of various factors, pharmacokinetic (PK) properties were studied in healthy male individuals, using the same medicinal products, methods of quantitative determination of drug plasma concentration, and calculations of PK parameters. The demographic characteristics of the study subjects were summarized and assessed using descriptive statistics, the Wilcoxon rank-sum test, or the Fisher exact test. The numbers of subjects experiencing AEs were compared between doses using the Fisher exact test or the Kruskal-Wallis test, and P values o0.05 were considered statistically significant. All PK parameters were summarized using descriptive statistics. Statistical comparison was performed using ANOVA, with a linear mixed-effects model. The fixed effects included in this model were the subject effect, the dose received, the period in which each dose was given, as well as the sequence in which the 2 doses were received. Proportionality was assumed if the 90% CI of the dose-normalized GMR of AUCt was within the 80.0% to 125.0% range. Analysis of the PK data was performed using WinNonlin version 5.3 (Pharsight Corporation, Mountain View, California). Statistical evaluation was conducted using SPSS Statistics version 20 (IBM SPSS Statistics, IBM Corporation, Armonk, New York).
Tolerability Assessments Tolerability was evaluated through the assessment of AEs, standard laboratory evaluations, and vital signs. The regular monitoring and recording of all AEs included any symptoms, their time of onset and resolution, duration, severity, and relationship to the study drug. Routine blood chemistry analysis, blood cell counts with white blood cell differential, urinalyses, physical examinations, ECGs, and vital
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RESULTS Subject Characteristics As shown in Figure 1, a total of 15 healthy, male, Korean volunteers participated in this study, and 12 subjects completed the crossover phase and received a single oral dose of the assigned treatment on days 1 and 15. Three volunteers dropped out of this trial (laboratory abnormality [n ¼ 1], withdrawal of
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N = 15 Volunteer screened N=3 Screening failures Reasons: Lab. abnormality (1) Consent withdrawn (1) ineligible (1)
N = 12 Subjects randomized
N=6 Group 1 - amitriptyline hydrochloride 10 mg
N=6 Group 2 - amitriptyline hydrochloride 25 mg
2 wk washout
2 wk washout
N=6 Group 1 - amitriptyline hydrochloride 25 mg
N=6 Group 2 - amitriptyline hydrochloride 10 mg
N = 12 Completed
Figure 1. Flow diagram of this study of single-dose, oral administration of amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects.
Table I. Baseline demographic and clinical characteristics in this study of amitriptyline hydrochloride in healthy, male, Korean subjects. Characteristic Age, y Height, cm Weight, kg Substance intake Alcohol (yes/no) Smoking (nicotine) (yes/no) Caffeine (yes/no)
Group 1* (n ¼ 6)
Group 2† (n ¼ 6)
All Patients (N ¼ 12)
P
22.2 (1.7) 176.0 (5.3) 70.2 (12.6)
21.2 (2.1) 173.0 (4.6) 63.2 (2.6)
21.7 (1.9) 174.5 (5.0) 66.7 (9.4)
0.323‡ 0.421‡ 0.200‡
4/2 0/6 5/1
3/3 0/6 2/4
7/5 0/12 7/5
1.0§ 1.0§ 0.242§
*
Received amitriptyline hydrochloride 10 mg in study period 1 and 25 mg in study period 2. Received amitriptyline hydrochloride 25 mg in study period 1 and 10 mg in study period 2. ‡ Wilcoxon rank sum test. § Fisher exact test. †
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Y. Nam et al. consent [n ¼ 1], and lack of eligibility [n ¼ 1]). The baseline characteristics of the 12 subjects are listed in Table I. Their mean (SD) age, height, and weight were 21.7 (1.9) years, 174.5 (5.0) cm, and 66.7 (9.4) kg, respectively.
Tolerability All of the subjects received the amitriptyline hydrochloride tablets according to the protocol, under supervision of Min-Gul Kim. Amitriptyline hydrochloride was well tolerated when administered orally at doses of 10 and 25 mg, and no serious AEs were reported during this study. As summarized in Table II, a total of 5 AEs occurred in 4 subjects. After the administration of amitriptyline hydrochloride 10 mg, 2 subjects reported 3 AEs; after the administration of amitriptyline hydrochloride 25 mg, 2 subjects reported 2 AEs. It was determined that drug administration may have had a causal relationship with the 4 reported events (dizziness [2 subjects in the 10-mg group] and asthenia [1 subject each in the 10- and 25-mg groups]). All of the AEs were rated as mild, and all subjects recovered without intervention.
Pharmacokinetic Properties and Statistical Analysis The mean plasma concentration–time profiles after a single oral dose of the study drug are shown in Figure 2.
The PK parameters are summarized in Table III. Dose proportionality between the 2 strengths (10 and 25 mg) of amitriptyline hydrochloride was observed in the mean values of Cmax and AUC. The Cmax, AUClast, and AUC0–1 values of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng h/mL, and 109.74 ng h/mL, respectively. The Cmax, AUClast, and AUC0–1 of amitriptyline 25 mg were 17.69 ng/mL, 260.68 ng h/mL, and 296.87 ng h/mL. As shown in Figure 3 and Table IV, linear regression analysis revealed significant linearity in Cmax, AUClast, and AUC0–1. In addition, we determined that the point estimate values of the dose-normalized GMRs of Cmax, AUClast, and AUC0–1 were within the predetermined 90% CI range for relative bioavailability with regard to dose proportionality (Table V).
DISCUSSION There have been few reports on the dose proportionality of the PK properties of amitriptyline hydrochloride in healthy Korean subjects. This clinical study was designed to evaluate and compare relative bioavailability with regard to dose proportionality between the 2 marketed strengths (10 and 25 mg) of amitriptyline hydrochloride tablets after single-dose administration in fasting, healthy, male, Korean subjects. Amitriptyline is readily absorbed in the gastrointestinal tract and is metabolized in the liver.18 It is
Table II. Adverse events reported with single-dose administration of amitriptyline hydrochloride 10 or 25 mg tablets in healthy, male, Korean subjects.* Parameter No. of subjects No. of AEs Nerve system disorders Dizziness General disorders and administration site condition Asthenia
10 mg (n ¼ 6)
25 mg (n ¼ 6)
All Patients (N ¼ 12)
P
2 3
2 2
4 5
1.0† 0.929‡
2§
1
—
—
1§
1§
—
—
*
None of the AEs were considered serious by the investigator; all AEs were rated as mild. Fisher’s exact test. ‡ Kruskal-Wallis test. § Considered by the investigator possibly treatment related. †
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25
Plasma Concentration (ng/mL)
20
10 mg 25 mg
15
10
5
0 0 2 4 6 8 1012
24
36 Time (h)
48
72
Figure 2. Mean (SD) plasma drug concentration–time curves after single-dose, oral administration of amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects.
Table III. Pharmacokinetic properties of single-dose amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects. Property Cmax Mean (SD), ng/mL Cmax/D, mean (SD), ng/mL %CV AUClast Mean (SD), ng h/mL AUClast/D, mean (SD), ng h/mL %CV AUC0–1 Mean (SD), ng h/mL AUC0–1, mean (SD), ng h/mL %CV t½, h Mean (SD) %CV Tmax, h* Mean (SD) Median (range) %CV
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10 mg (n ¼ 6)
25 mg (n ¼ 6)
5.96 (1.40) 0.60 (0.14) 23.41
17.69 (5.27) 0.71 (0.21) 29.81
91.35 (25.88) 9.14 (2.59) 28.33
260.68 (111.57) 10.43 (4.46) 42.80
109.74 (37.80) 10.97 34.44
296.87 (124.99) 11.87 (5.00) 42.10
26.47 (5.64) 21.29
24.79 (3.22) 12.98
3.50 (0.90) 3.50 (2.0–6.0) 25.84
3.31 (0.61) 3.25 (2.0–4.0) 19.45
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Y. Nam et al.
30 25
Cmax (ng/mL)
B
Dose vs Cmax Regression line 95% CI
600
Dose vs AUClast Regression line 95% CI
500 AUClast (ng.h/mL)
A
20 15 10
400 300 200 100
5 0
10
0
25
10
Dose (mg)
C
600
AUC0– (ng.h/mL)
500
25 Dose (mg)
Dose vs AUC0– Regression line 95% CI
400 300 200 100 0
10
25 Dose (mg)
Figure 3. Linear regression profile of dose-Cmax (A), dose-AUClast (B) and dose-AUC0–1 (C) after single-dose, oral administration of amitriptyline hydrochloride 10 or 25 mg in healthy, male, Korean subjects.
widely distributed throughout the body and excreted in the urine.19 The absorption, distribution, metabolism, and excretion process of this drug may be affected by a variety of factors, and the fact that this trial adhered to a single-dose, openlabel design and was performed in these selected healthy Korean subjects under carefully controlled conditions should be taken into account when interpreting the results.
In this study, amitriptyline hydrochloride was well tolerated. Although some subjects experienced AEs, none were serious. The lack of serious AEs may have been due to the low doses of amitriptyline hydrochloride administered in this study. A single dose of 10 or 25 mg is lower than the typical dose of 150 mg/d. It has been shown previously that a low dosage of amitriptyline (75 mg/d) was associated with fewer AEs than was a higher dose (150 mg/d).20,21 Dose
Table IV. Linear regression analysis of single-dose administration of 10 and 25 mg amitriptyline hydrochloride in healthy, male, Korean subjects. Slope Parameter Cmax AUClast AUC0–1
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y-Intercept
Value
95% CI
P
Value
95% CI
P
0.782 11.288 12.475
0.546 to 0999 6.717 to 15.860 7.234 to 17.687
o0.001 o0.001 o0.001
–1.855 –21.529 –15.012
–6.000 to 2.288 –108.565 to 65.507 –114.240 to 84.272
0.363 0.613 0.757
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Table V. ANOVA regression model of single-dose amitriptyline hydrochloride 10 and 25 mg in healthy, male, Korean subjects. Parameter Cmax AUClast AUC0–1
GMR
90% CI
1.1621 1.1002 1.0585
1.0554–1.2796 0.9952–1.2163 0.9369–1.1960
GMR ¼ geometric mean ratio.
proportionality between the 2 strengths (10 and 25 mg) of amitriptyline hydrochloride was observed in the mean values of Cmax and AUC, indicating that the 2 strengths amitriptyline hydrochloride (10 and 25 mg) have linear PK properties, and that 10 and 25 mg of amitriptyline hydrochloride were dose proportional in these healthy, male, Korean subjects. Although only 2 strengths were tested, our results suggest that systemic exposure to amitriptyline hydrochloride of increasing strengths will yield a predictable and linear increase in plasma drug concentration. In a previous study, the linearity of the kinetics of twice-daily amitriptyline were tested in 135 depressed patients, by measuring plasma concentrations.22 Although there was a linear relationship between the dose ratios and the concentration ratios, there may have been nonlinear kinetics in some patients, as the ratio between the concentration/dose ratios at low and high dosages was 41. An investigation of the disposition of amitriptyline after the administration of a single dose, as well as after long-term administration, suggested that there have been some of the discrepancies in the mean values of the PK parameters of amitriptyline.23 Broad individual variability in the elimination rate of amitriptyline has also been confirmed.23 The significant interindividual differences in amitriptyline PK properties in humans have been associated with genetic polymorphisms in the cytochrome (CYP) 2D6 isozyme. CYP2D6 has a key role in the metabolism of TCAs.24 It is well known that CYP2D6 activity is limited in 7% of the white population and in 1% to 3% of other ethnic groups.25 The results obtained in studies in healthy Korean subjects serve as a key point for the evaluation of the
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efficacy and tolerability of medical products in clinical use. However, the extrapolation of the data obtained in this clinical trial may limit the generalizability of our findings in the general population because of the complexities of the inclusion/exclusion criteria, dietary restrictions in the study protocol, and ethnic differences between the Korean and general populations.
CONCLUSIONS The exposure to amitriptyline hydrochloride was proportional over the low-dose therapeutic range of 10 to 25 mg in these healthy, male, Korean subjects, with a dose-proportional increase in the overall exposure to amitriptyline hydrochloride and the Cmax achieved. Tmax values in plasma were similar between the 10- and 25-mg doses. Based on these findings, a predictable and linear increase in systemic exposure can be expected in the tested doses of amitriptyline. Amitriptyline hydrochloride was well tolerated in these healthy, male, Korean volunteers.
ACKNOWLEDGMENTS The study was conducted at the Clinical Trial Center at Chonbuk National University Hospital. The sponsor monitored the study but had no role in conducting the study procedures, data analyses, or interpretation. Drs. Nam and Lim contributed equally to this work. Dr. Lim was the principal investigator of the trial. Drs. S.J. Chung, Y.H. Chung, Shin, Min-Gul Kim, and Sohn equally contributed to the study design and to the data analyses. Dr. Nam and Lee contributed to the review of the data analyses, literature search, figure/table creation, and manuscript writing. Dr. Hyoung-Chun Kim helped to revise the manuscript. Prof. Jeong made the final decision regarding manuscript submission.
CONFLICTS OF INTEREST This study was funded by Dong-Hwa Pharmaceutical Corporation (Seoul, Korea), manufacturers of amitriptyline hydrochloride. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
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Address correspondence to: Ji Hoon Jeong, PhD, Department of pharmacology, College of medicine, Chung-ang University, Heuk-seok 156-756, Dong-jak gu, Seoul, Republic of Korea. E-mail: [email protected]
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