Bioequivalence of two intravenous formulations of antithrombin III

A two-way crossover study in healthy Korean subjects

Kyoung Ah Kim, Yoon Young Lim, Sun Ho Kim, Ji-Young Park

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. Objective The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. Methods A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. Results Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC last, and AUC0-∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994-1.14053) for Cmax, 1.11305 (1.05435-1.17503) for AUClast, and 1.11527 (1.03754-1.19889) for AUC0-∞; corresponding values for AT-III Ag were 1.08802 (1.06258-1.11405), 1.10905 (1.05804-1.16242), and 1.11460 (1.02058-1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. Conclusion The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.

Original languageEnglish
Pages (from-to)1752-1761
Number of pages10
JournalClinical Therapeutics
Volume35
Issue number11
DOIs
Publication statusPublished - 2013 Nov 1

Fingerprint

Therapeutic Equivalency
Antithrombin III
Cross-Over Studies
Healthy Volunteers
Antigens
Pharmacokinetics
Antithrombin III Deficiency
Partial Thromboplastin Time
Vital Signs
Prothrombin Time
Marketing
Pharmaceutical Preparations
Physical Examination
Area Under Curve
Sepsis
Electrocardiography
Therapeutics

Keywords

  • antithrombin III
  • bioequivalence
  • pharmacokinetic equivalence
  • pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Bioequivalence of two intravenous formulations of antithrombin III : A two-way crossover study in healthy Korean subjects. / Kim, Kyoung Ah; Lim, Yoon Young; Kim, Sun Ho; Park, Ji-Young.

In: Clinical Therapeutics, Vol. 35, No. 11, 01.11.2013, p. 1752-1761.

Research output: Contribution to journalArticle

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title = "Bioequivalence of two intravenous formulations of antithrombin III: A two-way crossover study in healthy Korean subjects",
abstract = "Background Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. Objective The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. Methods A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. Results Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC last, and AUC0-∞ of AT-III activity were, respectively, 279.24{\%} (35.92), 14,364.10 (2325.25) {\%}·h, and 17,526.38 (3150.81) {\%}·h with the test formulation and 249.75{\%} (31.96), 12,962.95 (1897.52) {\%}·h, and 15,957.67 (3189.21) {\%}·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90{\%} CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994-1.14053) for Cmax, 1.11305 (1.05435-1.17503) for AUClast, and 1.11527 (1.03754-1.19889) for AUC0-∞; corresponding values for AT-III Ag were 1.08802 (1.06258-1.11405), 1.10905 (1.05804-1.16242), and 1.11460 (1.02058-1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. Conclusion The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.",
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T1 - Bioequivalence of two intravenous formulations of antithrombin III

T2 - A two-way crossover study in healthy Korean subjects

AU - Kim, Kyoung Ah

AU - Lim, Yoon Young

AU - Kim, Sun Ho

AU - Park, Ji-Young

PY - 2013/11/1

Y1 - 2013/11/1

N2 - Background Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. Objective The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. Methods A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. Results Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC last, and AUC0-∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994-1.14053) for Cmax, 1.11305 (1.05435-1.17503) for AUClast, and 1.11527 (1.03754-1.19889) for AUC0-∞; corresponding values for AT-III Ag were 1.08802 (1.06258-1.11405), 1.10905 (1.05804-1.16242), and 1.11460 (1.02058-1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. Conclusion The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.

AB - Background Treatment with antithrombin (AT)-III is indicated for patients with sepsis or hereditary AT deficiency. Objective The purpose of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of 2 AT-III formulations in healthy Korean volunteers to satisfy the regulatory requirements for bioequivalence for marketing purposes. Methods A single-center, single-dose, open-label, randomized, 2-period, 2-sequence crossover study was conducted in healthy Korean volunteers. Blood samples for the drug analysis were collected for up to 216 hours after drug administration. Participants received either the test or reference formulation of AT-III 100 U/kg IV for 20 minutes in the first period and the alternative formulation in the second period. Both the AT-III activity and antigen (Ag) were measured for the analysis of pharmacokinetic properties, and the prothrombin time and the activated partial thromboplastin time were assessed for the analysis of pharmacodynamic properties. Because AT-III is an endogenous compound, the analysis used data corrected from baseline values. The tolerability of the 2 formulations was also assessed based on physical examinations including vital sign measurements, laboratory tests, and 12-lead ECG. Results Of the 20 subjects enrolled (mean [SD] age, height, and weight, 25.3 [2.3] years, 175.3 [4.5] cm, and 67.4 [6.3] kg, respectively), 19 completed both treatment periods; 1 subject withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC last, and AUC0-∞ of AT-III activity were, respectively, 279.24% (35.92), 14,364.10 (2325.25) %·h, and 17,526.38 (3150.81) %·h with the test formulation and 249.75% (31.96), 12,962.95 (1897.52) %·h, and 15,957.67 (3189.21) %·h with the reference formulation. The observed mean (SD) Cmax, AUClast, and AUC0-∞ of AT-III Ag were 62.58 (5.66) mg/dL, 3051.94 (401.87) mg/dL·h, and 3639.80 (726.01) mg/dL·h, respectively, with the test formulation and 58.63 (5.27) mg/dL, 2805.08 (272.38) mg/dL·h, and 3340.00 (428.46) mg/dL·h with the reference formulation. The geometric mean ratios (90% CI) of the log-transformed data for AT-III activity between the 2 formulations were 1.11494 (1.08994-1.14053) for Cmax, 1.11305 (1.05435-1.17503) for AUClast, and 1.11527 (1.03754-1.19889) for AUC0-∞; corresponding values for AT-III Ag were 1.08802 (1.06258-1.11405), 1.10905 (1.05804-1.16242), and 1.11460 (1.02058-1.21726). During the study period, 8 adverse events were reported, and all were transient, mild, and resolved completely during the treatment period. Conclusion The results of the present study showed that these 2 AT-III formulations met the regulatory criteria for pharmacokinetic bioequivalence with respect to AT-III activity and Ag in these healthy Korean subjects. ClinicalTrials.gov identifier: NCT00846274.

KW - antithrombin III

KW - bioequivalence

KW - pharmacokinetic equivalence

KW - pharmacokinetics

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