Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects

A randomized, open-label, two-period, comparative, crossover study

Ji-Young Park, Kyoung Ah Kim, Pil Whan Park, Ock Je Lee, Jong Hyeon Ryu, Geun Hyeog Lee, Mun Choun Ha, Jin Sun Kim, Seoung Woo Kang, Kyung Ryul Lee

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc® [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80% to 125%. Results: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21-26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUClast), and AUC from 0 to infinity (AUC0-∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log*transformed Cmax, AUCO0-∞, and AUClast were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.

Original languageEnglish
Pages (from-to)1837-1847
Number of pages11
JournalClinical Therapeutics
Volume28
Issue number11
DOIs
Publication statusPublished - 2006 Nov 1

Fingerprint

Amlodipine
Cross-Over Studies
Pharmacokinetics
Korea
Area Under Curve
Urinalysis
Hematology
Blood Pressure
Pharmaceutical Preparations
Biochemistry
Electrocardiography
Heart Rate
Safety
Weights and Measures
Ideal Body Weight
Calcium Channel Blockers
Calcium Channels
Medical Schools

Keywords

  • amlodipine
  • chiral drug
  • chiral switching
  • enantiomer
  • S-amlodipine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects : A randomized, open-label, two-period, comparative, crossover study. / Park, Ji-Young; Kim, Kyoung Ah; Park, Pil Whan; Lee, Ock Je; Hyeon Ryu, Jong; Hyeog Lee, Geun; Choun Ha, Mun; Sun Kim, Jin; Woo Kang, Seoung; Ryul Lee, Kyung.

In: Clinical Therapeutics, Vol. 28, No. 11, 01.11.2006, p. 1837-1847.

Research output: Contribution to journalArticle

Park, Ji-Young ; Kim, Kyoung Ah ; Park, Pil Whan ; Lee, Ock Je ; Hyeon Ryu, Jong ; Hyeog Lee, Geun ; Choun Ha, Mun ; Sun Kim, Jin ; Woo Kang, Seoung ; Ryul Lee, Kyung. / Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects : A randomized, open-label, two-period, comparative, crossover study. In: Clinical Therapeutics. 2006 ; Vol. 28, No. 11. pp. 1837-1847.
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title = "Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects: A randomized, open-label, two-period, comparative, crossover study",
abstract = "Background: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20{\%} of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc{\circledR} [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80{\%} to 125{\%}. Results: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21-26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUClast), and AUC from 0 to infinity (AUC0-∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90{\%} Cls for the corresponding ratios of log*transformed Cmax, AUCO0-∞, and AUClast were 97.56{\%} to 112.51{\%}, 86.31{\%} to 98.74{\%}, and 83.46{\%} to 100.04{\%}, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.",
keywords = "amlodipine, chiral drug, chiral switching, enantiomer, S-amlodipine",
author = "Ji-Young Park and Kim, {Kyoung Ah} and Park, {Pil Whan} and Lee, {Ock Je} and {Hyeon Ryu}, Jong and {Hyeog Lee}, Geun and {Choun Ha}, Mun and {Sun Kim}, Jin and {Woo Kang}, Seoung and {Ryul Lee}, Kyung",
year = "2006",
month = "11",
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doi = "10.1016/j.clinthera.2006.11.008",
language = "English",
volume = "28",
pages = "1837--1847",
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TY - JOUR

T1 - Pharmacokinetic and pharmacodynamic characteristics of a new S-amlodipine formulation in healthy Korean male subjects

T2 - A randomized, open-label, two-period, comparative, crossover study

AU - Park, Ji-Young

AU - Kim, Kyoung Ah

AU - Park, Pil Whan

AU - Lee, Ock Je

AU - Hyeon Ryu, Jong

AU - Hyeog Lee, Geun

AU - Choun Ha, Mun

AU - Sun Kim, Jin

AU - Woo Kang, Seoung

AU - Ryul Lee, Kyung

PY - 2006/11/1

Y1 - 2006/11/1

N2 - Background: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc® [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80% to 125%. Results: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21-26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUClast), and AUC from 0 to infinity (AUC0-∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log*transformed Cmax, AUCO0-∞, and AUClast were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.

AB - Background: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. Methods: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg PO) (Lodien™ [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg PO) (Norvasc® [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80% to 125%. Results: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21-26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUClast), and AUC from 0 to infinity (AUC0-∞) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng - h/mL, and 175.3 [45.1] ng - h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng - h/mL, and 161.7 [43.8] ng - h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log*transformed Cmax, AUCO0-∞, and AUClast were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. Conclusions: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.

KW - amlodipine

KW - chiral drug

KW - chiral switching

KW - enantiomer

KW - S-amlodipine

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