Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects

CLINICAL THERAPEUTICS® / VOL. 26, NO. 5, 2004

Randomized, Open-Label,Two-Period Crossover Comparison of the Pharmacokinetic and Pharmacodynamic Properties of Two Amlodipine Formulations in Healthy Adult Male Korean Subjects Ji-Young Park, MD, PhD,1 Kyoung-Ah Kim, PhD,1 Gwan-Sun Lee, PhD,2 Pil-Whan Park, MD, PhD,3 Su-Lyun Kim, BS,1 Young-Suk Lee, MD,2 Young-Wook Lee, PhD,2 and Eak-Kyun Shin, MD, PhD4 1Department

of Pharmacology, Clinical Trial Center, Gil Medical Center, Gachon Medical School, Incheon, 2Clinical Research Department and Central Research Institute, Hanmi Pharmaceutical Co., Ltd., Seoul, and Departments of 3Laboratory Medicine and 4Internal Medicine, Gil Medical Center, Incheon, Korea ABSTRACT

Background: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility—and improved stability against long-term stability test and accelerated temperature test—compared with the conventional formulation (amlodipine besylate). Objective: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. Methods: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. Results: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20–25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57–77 kg). The plasma concentration–time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration–time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. Conclusions: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects. (Clin Ther. 2004;26:715–723) Copyright © 2004 Excerpta Medica, Inc. Key words: amlodipine, bioavailability, bioequivalence, pharmacokinetics, pharmacodynamics. Accepted for publication March 4, 2004. Printed in the USA. Reproduction in whole or part is not permitted.

Copyright © 2004 Excerpta Medica, Inc.

0149-2918/04/$19.00

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INTRODUCTION

Study Population

Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. Its pharmacokinetic (PK) profile differs from that of other dihydropyridine calcium antagonists.1–3 In particular, amlodipine has a lower hepatic extraction ratio and, consequently, higher bioavailability. In addition, because it has high tissue affinity, amlodipine is taken up by hepatic tissue and then redistributed into the systemic circulation,4,5 resulting in a longer time to peak plasma concentration (Cmax) (6–12 hours) and a longer plasma terminal half-life (t1/2) (30–50 hours) compared with other dihydropyridine calcium antagonists.1,2,6 The commercially available form of amlodipine* is conjugated with besylate salt to increase water solubility.7 A new amlodipine formulation,† in which the free base of amlodipine is conjugated with the chemically different salt camsylate, has been developed (unpublished observations, Hanmi Pharmaceutical Co., Seoul, Korea, 2003)8 and is similar in terms of physical properties, melting point, and solubility to the conventional formulation (amlodipine besylate) but has improved stability in long-term stability and accelerated temperature tests.8 Preclinical studies showed no significant difference between the 2 formulations in dissolution profiles, toxicities in vitro,8 PK properties, or blood pressure (BP)–lowering effect in animals (unpublished observations, Hanmi Pharmaceutical Co., Seoul, Korea, 2003). The present study was designed to assess and compare the PK and pharmacodynamic (PD) properties and safety profiles of the new amlodipine formulation with the conventional formulation in healthy male subjects.

Healthy male Korean volunteers aged 20 to 40 years were eligible to participate in the study if their body weight was within 10% of ideal and they were judged by physicians to be healthy based on the results of a detailed physical examination, 12-lead electrocardiography (ECG), serum biochemistry, hematology, and routine urinalysis. Subjects were not eligible if they had a history of (or evidence of ) hepatic, renal, gastrointestinal, or hematologic abnormality; hepatitis B or C or HIV infection on screening examination; any other acute or chronic diseases; or known allergy to any drugs.

SUBJECTS AND METHODS Study Design

This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Institutional review board approval was obtained for the study protocol, and all subjects provided written informed consent before the study. *Trademark: †Trademark:

Korea).

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Norvasc® (Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea). Amodipine® (Hanmi Pharmaceutical Co., Ltd., Seoul,

Study Procedures

All subjects were administered a single 5-mg oral dose of the reference formulation (amlodipine besylate) and the test formulation (amlodipine camsylate) separated by a 4-week washout period in a crossover manner. Each eligible subject received both study drugs; the order of administration was determined by the randomization schedule generated using SAS software version 6.12 (SAS Institute Inc., Cary, North Carolina) prior to the start of the study. Because the t1/2 of amlodipine is 30 to 50 hours,1–3 a washout period of 4 weeks was sufficient to minimize the potential carryover effect from the first study drug administration. Hematology, biochemistry, ECG, and urinalysis were performed at baseline and after study phase 2. All subjects were admitted to the clinical trial center the evening prior to the day of drug administration. The following morning, they were given a single oral dose of either the test or the reference formulation. An angiocatheter with normal saline lock was inserted into a vein in the antecubital area. Blood samples were collected immediately prior to drug administration (baseline) and then at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, and 144 hours after drug administration. Blood samples (8 mL) were collected in a heparinized tube after discarding 1 mL of blood from the angiocatheter. Plasma was separated by centrifugation at 3000 rpm at 4°C for 15 minutes within 30 minutes of collection and stored at –70°C until assayed, and the concentrations of amlodipine in plasma were analyzed within 10 days after the end of the study.

J.-Y. Park et al.

Pharmacodynamic Assessments

The primary variables measured in this study were systolic and diastolic BP (SBP and DBP, respectively) and pulse rate (PR) in a sitting position. Hematology, biochemistry, urinalysis, and ECG were performed at baseline and at the end of the study. Before administration of each formulation, baseline BP and PR were measured 3 times with the subject in a sitting position, and the mean value was used as the baseline value. After administration of amlodipine, BP and PR were measured just before each blood sampling. BP and PR were measured in the same patient’s arm by the same investigator at each visit, using an automatic BP monitor with a validated A&D UA-767 oscillometer (A&D Company, Ltd., Tokyo, Japan).9 Before the measurements were begun, each patient was seated comfortably for ≥5 minutes, with the arm supported at heart level. The cuff was placed on the upper arm. A built-in automatic compressor provided gradual, adaptive compression of the cuff, and the constant-airrelease valve system produced an appropriately stable rate of deflation. Bioanalysis

Plasma amlodipine concentrations were analyzed by LabFrontier Co. (Suwon, Korea) using a validated high-performance liquid chromatographic mass spectrometer (HPLC-MS). Briefly, plasma (1 mL) was added to 10-mL glass tubes containing the internal standard (ketoconazole, 100 µL of 25 ng/mL), and 100 µL of 0.1 M sodium carbonate and 6 mL of ethyl acetate were then added. After vigorous vortex mixing for 5 minutes, the mixture was centrifuged for 15 minutes at 3000 rpm at 4°C. The organic phase was transferred to a clean glass tube and evaporated to dryness under a flow of nitrogen gas. The dry residue was reconstituted with 80 µL of mobile phase, and a 50-µL aliquot of this solution was injected onto the HPLC-MS with an Ecka Kromasil C8 column (5 µm, 4.6 2 150 mm, Ecka, Sweden) and a Restek Ultra C18 guard cartridge (5 µm, 4.0 2 10 mm, Restek Corp., Bellefonte, Pennsylvania). The mobile phase was composed of a 10-mM ammonium formate buffer (pH 2.3, adjusted with formic acid) and acetonitrile (63:37, v/v). The mass spectrometer with electrospray source was run in the positive mode (ES+) and m/z 409.1 and 533.2 were monitored for amlodipine and internal standard, respectively.

A linearity calibration curve in the range of 0.1 to 10 ng/mL was established for amlodipine (r2 = 0.99997). Intraday coefficients of variation (CVs) were 6.1%, 3.3%, and 1.7% for amlodipine at concentrations of 0.1, 1, and 10 ng/mL, respectively. At the same concentrations, interday CVs were 5.9%, 4.2%, and 2.3%. The limit of quantification was 0.1 ng/mL. Safety Profile Analysis

The hematology, biochemistry, ECG, and urinalysis performed at baseline and after study phase 2 also were used to assess the safety profiles of the 2 drugs. In addition, adverse events (AEs) were monitored and recorded on case-report forms based on patient interview and physical examination. Statistical Analysis

The PK parameters of amlodipine were estimated by noncompartmental methods using WinNonlin software version 2.0 (Scientific Consulting Inc., Apex, North Carolina). The Cmax values and the time to reach Cmax (Tmax) were estimated directly from the observed plasma concentration–time data. The area under the plasma concentration–time curve from time 0 to 144 hours (AUClast) was calculated using the linear trapezoidal rule. The AUC from time 0 to infinity (AUC0–∞) was calculated as: AUC0–∞ = AUClast + Ct/Ke, where Ct is the last plasma concentration measured and Ke is the elimination rate constant; Ke was determined using linear regression analysis of the logarithmlinear part of the plasma concentration–time curve. The t1/2 of amlodipine was calculated as: t1/2 = ln2/Ke. The oral clearance (CL/F) of amlodipine was calculated as CL/F = dose/AUC0–∞. For hemodynamic measures, the areas under the effect-time curves from 0 to 24 hours (AUEC0–24) were calculated for individual subjects using the linear trapezoidal method. Maximum changes (∆max) in SBP, DBP, and PR were also determined for individual subjects. To determine whether the 2 amlodipine formulations were pharmacokinetically equivalent, we assessed the calculated individual Cmax, AUClast, and 717

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AUC0–∞, and their ratios (test/reference) using logtransformed data; their means and 90% CIs were analyzed by a parametric analysis of variance method using the SPSS software version 11.5 (SSPS Inc., Chicago, Illinois). Due to the nature of normal-theory CIs, this is equivalent to carrying out two 1-sided tests of a hypothesis at the 5% level of significance.7 The drugs were considered pharmacokinetically equivalent if the difference between 2 compared parameters was statistically nonsignificant (P ≥ 0.05) and the 90% CI for these parameters fell within 0.8 to 1.25. RESULTS

Eighteen healthy male Korean volunteers (mean [SD] age, 22.3 [1.5] years [range, 20–25 years]; mean [SD] body weight, 67.9 [5.6] kg; range, 57–77 kg) participated in the study. Results of hematology, biochemistry, ECG, and urinalysis at baseline and study end are shown in Table I.

Pharmacokinetic Analysis

Amlodipine appeared in the plasma of all participants within 1 hour after administration and achieved maximal concentrations between 4 and 12 hours. The mean plasma concentration–time curves for both amlodipine formulations are shown in Figure 1. The PK parameters are presented in Table II. No significant between-group differences were found in any of the parameters. Mean Cmax values were obtained after 6 and 7 hours and reached values of 3.6 and 3.7 ng/mL for the reference and test formulations, respectively. The mean AUC0–∞ values were 169.5 ng/mL·h for the reference formulation and 187.7 ng/mL·h for the test formulation. Amlodipine CL/F was 34.5 and 32.7 L/h for the reference and test formulations, respectively. The equivalence statistics of bioavailability for the PK parameters (Cmax, AUClast, and AUC0–∞) of the 2 amlodipine formulations are summarized in Table III. No statistically significant differences were found

Table I. Results of hematology, biochemistry, and urinalysis testing of study subjects (N = 18) at baseline and study end. Test Hematology Leukocyte count, cells × 103/L Hemoglobin, g/dL Hematocrit, % Erythrocyte count, cells × 106/L Platelet count, cells × 103/mm3 Biochemistry Calcium, mg/dL Chloride, mmol/L Glucose, mg/dL Potassium, mmol/L Sodium, mmol/L Phosphorus, mg/dL Alkaline phosphatase, U/L Alanine aminotransferase, U/L Aspartate aminotransferase, U/L Cholesterol, mg/dL Total bilirubin, mg/dL Blood urea nitrogen, mg/dL Creatinine, mg/dL Lactate dehydrogenase, U/L Creatine phosphokinase, IU/L Uric acid, mg/dL Urinalysis pH Specific gravity, g/mL

718

Baseline, Mean (SD)

6.7 15.0 44.3 5.1 276.9

(1.4) (1.1) (2.9) (0.3) (53.6)

End of Study, Mean (SD)

8.1 13.8 41.7 4.7 278.5

Normal Range

(0.4) (0.8) (1.9) (0.2) (40.3)

4–10 13–17 39–51 4.4–5.9 150–450

9.4 (0.4) 102.3 (1.7) 91.3 (9.4) 4.5 (0.3) 141.6 (1.0) 3.8 (0.4) 157.1 (33.6) 16.2 (5.2) 17.9 (2.4) 154.1 (19.5) 0.9 (0.2) 11.1 (2.3) 1.0 (0.1) 314.5 (73.2) 109.8 (33.1) 6.1 (0.9)

9.1 (0.1) 106.5 (0.7) 92.0 (5.7) 4.1 (0.3) 140.5 (0.7) 4.5 (0.3) 169.5 (3.5) 17.5 (0.7) 17.0 (1.4) 139.7 (15.3) 0.8 (0.2) 8.9 (0.6) 1.0 (0.0) 238.0 (18.4) 65.0 (21.2) 6.2 (0.3)

8.2–10.8 95–110 70–120 3.5–5.5 135–145 2.5–4.7 70–290 5–40 0–40 120–250 0.2–1.2 8–22 0.6–1.2 120–520 26–200 2.5–8.3

6.0 (0.6) 1.022 (0.007)

6.5 (0.7) 1.023 (0.006)

5.0–8.0 1.001–1.035

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Reference Test

Plasma Amlodipine Concentration (ng/mL)

5

4

3

2

1

0 0

24

48

72

96

120

144

Time (h)

Figure 1. Mean (SD) plasma amlodipine concentrations after administration of a single 5-mg oral dose of the reference (amlodipine besylate) and test (amlodipine camsylate) formulations of amlodipine in 18 healthy male subjects.

Table II.

Pharmacokinetic properties of amlodipine obtained from study subjects (N = 18) after administration of a single 5-mg dose of reference* and test† amlodipine formulations.‡ (Values are expressed as mean [SD] unless otherwise indicated.) Parameter Tmax, h Median Range Cmax, ng/mL Ke, h–1 t1/2, h AUClast, ng/mL·h AUC0–∞, ng/mL·h CL/F, L/h

Reference

Test

6 4–12 3.6 (1.6) 0.017 (0.003) 42.2 (9.0) 153.7 (62.7) 169.5 (67.4) 34.5 (15.0)

7 5–12 3.7 (1.8) 0.018 (0.004) 39.3 (7.8) 171.2 (77.0) 187.7 (83.5) 32.7 (16.2)

Tmax = time to peak plasma concentration; Cmax = peak plasma concentration; Ke = elimination rate constant; t1/2 = terminal half-life; AUClast = area under the plasma concentration–time curve, last available measurement; AUC0–∞ = area under the plasma concentration–time curve from time 0 to infinity; CL/F = oral clearance. *Amlodipine besylate. †Amlodipine camsylate. ‡No significant between-treatment differences were found.

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Table III. Equivalence statistics of bioavailability: treatment ratios of the log-transformed geometric mean pharmacokinetic parameters of the reference* and test† amlodipine formulations (N = 18 subjects). Parameter Cmax, ng/mL

Ratio, %

90% CI

99.6

88.7–111.8

AUClast, ng/mL·h

109.2

96.2–123.9

AUC0–∞, ng/mL·h

108.2

95.4–122.8

Cmax = peak plasma concentration; AUClast = area under the plasma concentration–time curve, last available measurement; AUC0–∞ = area under the plasma concentration–time curve from time 0 to infinity. *Amlodipine besylate. †Amlodipine camsylate.

between the 2 formulations in any parameter. The mean log-transformed ratios of the parameters and their 90% CIs were all within the predefined bioequivalence range of 80% to 125%. Pharmacodynamic Assessment

Figure 2 and Table IV show the changes in SBP, DBP, and PR after single-dose administration of either reference or test formulation in healthy male subjects. Compared with predose values, mean (SD) SBP decreased significantly during the 6- to 8-hour period following the administration of the reference (∆max, –13.8 [5.0] mm Hg; P < 0.001) and test (∆max, –12.3 [9.2] mm Hg; P < 0.001) formulations. DBP decreased significantly during the 1- to 12-hour period following administration of the reference (∆max, –14.8 [5.2] mm Hg; P < 0.001) and test (∆max, –15.2 [4.3] mm Hg; P < 0.001) formulations. PR increased significantly during the 5- to 12-hour period following administration of the reference (∆max, 11.4 [3.9] bpm; P < 0.001) and test (∆max, 10.9 [2.4] bpm; P < 0.001) formulations. However, no statistically significant differences in SBP, DBP, and PR were found between the 2 formulations (Figure 2 and Table IV). In addition, no significant differences were found between the formulations in either ∆max from baseline or the AUEC0–24 for SBP, DBP, and PR. The PD parameters for SBP, DBP, and PR are presented in Table IV. Safety Profiles

Although the cardiovascular effects of amlodipine changed BP and PR, no AEs were noted during the study. In addition, there were no clinically relevant changes in physical, hematologic, biochemical, or urinalysis findings between baseline and study end 720

(Table I). The overall ECG assessment was normal in all participants at baseline and the end of the study. DISCUSSION

The results of the present study showed that the 2 formulations of amlodipine were similar in hemodynamic and PK characteristics in healthy male Korean subjects. The test formulation was absorbed slowly, and peak plasma levels were reached between 5 and 12 hours after administration. The mean (SD) value for t1/2 obtained in this study was 39.3 (7.8) hours, which was comparable to that of the reference formulation (42.2 [9.0] hours). These results are consistent with the PK characteristics of previously reported data.10–12 AUC is accepted as a good indicator of the extent of absorption, whereas Cmax and Tmax are considered estimators of the rate of absorption.13 When 2 formulations of a drug are bioequivalent in rate and extent of absorption, it is assumed that they are therapeutically equivalent.14,15 Two internationally recognized organizations (the US Food and Drug Administration [FDA]16 and the European Agency for the Evaluation of Medicinal Products17), and the Korean FDA,18 have proposed that bioequivalence can be assumed only when the characteristic parameters of bioavailability show no more than a defined difference. It is generally accepted that the AUC and Cmax of a test formulation should lie within the 20% deviation of the reference formulation, so that the ratio of AUC and Cmax should be between 0.80 and 1.25 for logarithm-transformed data.19,20 Based on accepted regulatory requirements,12–14 the present study demonstrated that the 2 amlodipine formulations—5 mg of amlodipine besylate (reference) or amlodipine camsylate (test)—were pharma-

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Reference Test

A 5

D SBP (mm Hg)

0

–5

–10

–15 0

24

48

72

96

120

144

0

24

48

72

96

120

144

0

24

48

72

96

120

144

B 5

D DBP (mm Hg)

0

–5

–10

–15

C

D HR (bpm)

10

5

0

–5

Time (h)

Figure 2. Mean (SD) changes in systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), and pulse rate (PR) (C) after administration of a single 5-mg oral dose of reference (amlodipine besylate) and test (amlodipine camsylate) formulations of amlodipine in 18 healthy male subjects. No significant between-treatment differences were found. 721

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Table IV. Pharmacodynamic properties obtained from study subjects (N = 18) after a single 5-mg oral dose of reference* and test† formulations of amlodipine.‡ (Values are presented as mean [SD].) Parameter SBP Baseline, mm Hg§ ∆ AUEC0–24, mm Hg/h ∆ Mean SBP, mm Hg ∆max, mm Hg T∆max, h DBP Baseline, mm Hg§ ∆ AUEC0–24, mm Hg/h ∆ Mean DBP, mm Hg ∆max, mm Hg T∆max, h PR Baseline, bpm§ ∆ AUEC0–24, bpm/h ∆ Mean PR, bpm ∆max, bpm T∆max, h

Reference

Test

121.7 –90.7 –3.8 –13.8 11.9

(3.4) (78.4) (3.3) (5.0)\ (21.7)

121.8 –82.5 –3.4 –12.3 9.2

(3.4) (68.9) (2.9) (9.2)\ (10.1)

73.9 –104.4 –4.3 –14.8 6.4

(5.9) (63.0) (2.6) (5.2)\ (2.0)

76.6 –125.6 –5.2 –15.2 7.3

(6.2) (58.9) (2.5) (4.3)\ (1.6)

70.1 80.9 3.4 11.4 19.3

(4.6) (41.5) (1.7) (3.9)\ (28.4)

72.6 67.0 2.8 10.9 19.1

(5.3) (37.8) (1.6) (2.4)\ (28.5)

SBP = systolic blood pressure; ∆ AUEC0–24 = change in area under the effect-time curve from 0 to 24 hours; ∆max = maximal change in pharmacodynamic parameter;T∆max = time to ∆max; DBP = diastolic blood pressure; PR = pulse rate. *Amlodipine besylate. †Amlodipine camsylate. ‡No significant between-treatment differences were found. §Value is the mean of 3 measurements taken before administration of amlodipine. \P < 0.001 versus baseline.

cokinetically equivalent in healthy subjects after single administration in a crossover manner. The 90% CIs of Cmax, AUClast, and AUC0–∞ of the ratio of the 2 formulations were all in the stipulated 0.80 to 1.25 range,19,20 indicating PK equivalence of the 2 amlodipine formulations. The hemodynamic data obtained indicated that a single 5-mg dose of amlodipine was sufficient to achieve a significant reduction in BP in healthy male subjects, and these results were consistent with previously reported data.10 However, PD analysis, including SBP, DBP, and PR, showed no statistically significant difference between the 2 amlodipine formulations. Taken together, these results suggest that both amlodipine formulations may be pharmacokinetically and therapeutically equivalent in healthy male subjects. CONCLUSIONS

Based on accepted regulatory requirements for bioequivalence, the test formulation (amlodipine camsy722

late) was pharmacokinetically equivalent in terms of both rate and extent of absorption to the reference formulation (amlodipine besylate) in healthy male Korean subjects. The treatment ratios of the geometric means and 90% CIs for Cmax, AUClast, and AUC0–∞ were all within the predetermined 80% to 125% range for PK equivalence. Both formulations showed similar PD characteristics, including effects on SBP, DBP, and PR, and no AEs were found during the study. REFERENCES 1. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J. 1989;118:1100–1103. 2. Meredith PA, Elliott HL. Clinical pharmacokinetics of amlodipine. Clin Pharmacokinet. 1992;22:22–31. 3. Haria M, Wagstaff AJ. Amlodipine. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs. 1995;50:560– 586.

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4. Beresford AP, McGibney D, Humphrey MJ, et al. Metabolism and kinetics of amlodipine in man. Xenobiotica. 1988;18:245–254. Walker DK, Humphrey MJ, Smith DA. Importance of 5. metabolic stability and hepatic distribution to the pharmacokinetic profile of amlodipine. Xenobiotica. 1994;24:243–250. 6. Stopher DA, Beresford AP, Macrae PV, Humphrey MJ. The metabolism and pharmacokinetics of amlodipine in humans and animals. J Cardiovasc Pharmacol. 1988;12(Suppl 7):S55–S59. 7. Arrowsmith JE, Campbell SF, Cross PE, et al. Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents. J Med Chem. 1986;29:1696–1702. 8. Kim BH, Seo HW, Kim MS. Antihypertensive effects of amlodipine besylate and its new salts. J Appl Pharmacol. 2003;11:133–138. 9. Rogoza AN, Pavlova TS, Sergeeva MV. Validation of A&D UA-767 device for the self-measurement of blood pressure. Blood Press Monit. 2000;5:227–231. 10. Josefsson M, Zackrisson AL, Ahlner J. Effect of grapefruit juice on the pharmacokinetics of amlodipine in healthy volunteers. Eur J Clin Pharmacol. 1996;51:189–193. 11. Vincent J, Harris SI, Foulds G, et al. Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine. Br J Clin Pharmacol. 2000; 50:455–463. 12. Faulkner JK, McGibney D, Chasseaud LF, et al. The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14

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repeated oral doses given once daily. Br J Clin Pharmacol. 1986;22:21–25. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987;15:657–680. Farolfi M, Powers JD, Rescigno A. On the determination of bioequivalence. Pharmacol Res. 1999;39:1–4. Meredith P. Bioequivalence and other unresolved issues in generic drug substitution. Clin Ther. 2003; 25:2875–2890. Food and Drug Administration. Guidance: Statistical Procedure for Bioequivalence Studies Using Standard 2Treatment Cross-over Design: Statement under 21 CFR 10.0. Rockville, Md: US Dept of Health and Human Services; 1992. Committee for Proprietary Medicinal Products (CPMP) Working Party on the Efficacy of Medicinal Products. Note for Guidance: Investigation of Bioavailability and Bioequivalence. Brussels; 1991. Food and Drug Administration of Korea (KFDA). Korean FDA Guidelines for Bioequivalence Test. Seoul, Korea: KFDA; 1996. Meyer MC. United States Food and Drug Administration requirements for the approval of generic drug products. J Clin Psychiatry. 2001;62(Suppl 5):4–9. Approved Drug Products with Therapeutic Equivalence Evaluations. Food and Drug Administration Web site. Available at: http://www.fda.gov/ cder/ob/docs/preface/ecpreface.htm. Accessed March 18, 2003.

Address correspondence to: Ji-Young Park, MD, PhD, Department of Pharmacology, Clinical Trial Center, Gil Medical Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Korea. E-mail: [email protected] 723