Cited by 286Atrial Fibrillation Management and OutcomesBlood Coagulation and Thrombosis MechanismsVenous Thromboembolism Diagnosis and Management

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Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factorXa inhibitor, in healthy subjects

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Frost, Charles, Nepal, Sunil, Wang, Jessie, Schuster, Alan, Byon, Wonkyung, Boyd, Rebecca A., Yu, Zhigang, Shenker, Andrew, Barrett, Yu Chen, Mosqueda‐Garcia, Rogelio, LaCreta, Frank·2013·British Journal of Clinical Pharmacology

DOI 10.1111/bcp.12106PMC PMC3853536

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Abstract

AIM: Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. METHOD: This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). RESULTS: Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile. CONCLUSION: Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

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Authors: Frost, C., Nepal, S., Wang, J., Schuster, A., Byon, W., Boyd, R. A., Yu, Z., Shenker, A., Barrett, Y. C., Mosqueda‐Garcia, R., & LaCreta, F.
Affiliations: Princeton University (US)
Pfizer (United States) (US)
Corresponding author: Frost, Charles
ORCID: Wang, Jessie
Byon, Wonkyung
Yu, Zhigang
LaCreta, Frank
Venue: British Journal of Clinical Pharmacology
Publisher: Wiley
Published: 2013-10-21
Volume: 76
Issue: 5
Pages: 776-786
ISSN: 0306-5251 (ISSN-L)
1365-2125
DOI: 10.1111/bcp.12106
PMC: PMC3853536
OpenAlex: W1568662837
Cited by: 286
References: 35
Citations by year: 2026: 11 · 2025: 10 · 2024: 14 · 2023: 23 · 2022: 15 · 2021: 30 · 2020: 22 · 2019: 23 · 2018: 20 · 2017: 24 · 2016: 34 · 2015: 30 · 2014: 19 · 2013: 11
FWCI: 21.28
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: British Journal of Clinical Pharmacology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Bristol-Myers Squibb
Pfizer Inc
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
Keywords: apixaban, factor Xa inhibitors, pharmacokinetics, pharmacodynamics, multiple oral doses, dose escalation, safety and tolerability, anticoagulation, international normalized ratio, activated partial thromboplastin time, prothrombin time, steady-state concentration, peak-to-valley ratio, dosing regimen
MeSH terms: Administration, Oral, Adult, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Fibrinolytic Agents, Humans, Male, Partial Thromboplastin Time, Prothrombin Time, Pyrazoles, Pyridones, International Normalized Ratio, Young Adult, Factor Xa Inhibitors

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Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factorXa inhibitor, in healthy subjects

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