A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban

Charles Frost,1 Yan Song,1 Yu Chen Barrett,1 Jessie Wang,2 Janice Pursley,3 Rebecca A Boyd,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, 2Exploratory Development Global Biometric Sciences, 3Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, Princeton, NJ, U...

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Main Authors: Frost C, Song Y, Barrett YC, Wang J, Pursley J, Boyd RA, LaCreta F
Format: Article
Language:English
Published: Dove Medical Press 2014-11-01
Series:Clinical Pharmacology : Advances and Applications
Online Access:http://www.dovepress.com/a-randomized-direct-comparison-of-the-pharmacokinetics-and-pharmacodyn-peer-reviewed-article-CPAA
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spelling doaj-17193646f7134bbe8f4f813d423d9e132020-11-24T23:21:42ZengDove Medical PressClinical Pharmacology : Advances and Applications1179-14382014-11-012014default17918719152A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxabanFrost CSong YBarrett YCWang JPursley JBoyd RALaCreta F Charles Frost,1 Yan Song,1 Yu Chen Barrett,1 Jessie Wang,2 Janice Pursley,3 Rebecca A Boyd,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, 2Exploratory Development Global Biometric Sciences, 3Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, Princeton, NJ, USA; 4Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc., Groton, CT, USA Background: Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. Objective: Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. Methods: In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. Results: Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0–24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0–24, Cmax, Cmin) was 20%–24% for apixaban versus 29%–46% for rivaroxaban. Peak AXA, AXA AUC(0–24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration–AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). Conclusion: Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined. Keywords: apixaban, pharmacodynamics, pharmacokinetics, rivaroxaban, safetyhttp://www.dovepress.com/a-randomized-direct-comparison-of-the-pharmacokinetics-and-pharmacodyn-peer-reviewed-article-CPAA
collection DOAJ
language English
format Article
sources DOAJ
author Frost C
Song Y
Barrett YC
Wang J
Pursley J
Boyd RA
LaCreta F
spellingShingle Frost C
Song Y
Barrett YC
Wang J
Pursley J
Boyd RA
LaCreta F
A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
Clinical Pharmacology : Advances and Applications
author_facet Frost C
Song Y
Barrett YC
Wang J
Pursley J
Boyd RA
LaCreta F
author_sort Frost C
title A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
title_short A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
title_full A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
title_fullStr A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
title_full_unstemmed A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
title_sort randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban
publisher Dove Medical Press
series Clinical Pharmacology : Advances and Applications
issn 1179-1438
publishDate 2014-11-01
description Charles Frost,1 Yan Song,1 Yu Chen Barrett,1 Jessie Wang,2 Janice Pursley,3 Rebecca A Boyd,4 Frank LaCreta1 1Exploratory Clinical and Translational Research, 2Exploratory Development Global Biometric Sciences, 3Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, Princeton, NJ, USA; 4Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc., Groton, CT, USA Background: Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders. Objective: Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban. Methods: In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods. Results: Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0–24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0–24, Cmax, Cmin) was 20%–24% for apixaban versus 29%–46% for rivaroxaban. Peak AXA, AXA AUC(0–24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration–AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001). Conclusion: Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined. Keywords: apixaban, pharmacodynamics, pharmacokinetics, rivaroxaban, safety
url http://www.dovepress.com/a-randomized-direct-comparison-of-the-pharmacokinetics-and-pharmacodyn-peer-reviewed-article-CPAA
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