Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor X a inhibitor, in healthy subjects
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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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The more favorable bleeding profile of apixaban is proposed to result from decreased peak-to-trough ratios afforded by twice-daily DOAC dosing.
“Hence, the more favorable bleeding profile is proposed to be a result of the decreased peak-to-trough ratios afforded by twice-daily DOAC dosing. 19”
From Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world (2019) · cites this paper as [19]
The Pharmacokinetics section reports a lower peak-to-trough ratio with twice-daily than once-daily apixaban dosing. But the Discussion says there is no definitive evidence that this difference provides a benefit, and the paper does not propose it as an explanation for a more favorable bleeding profile. (LLM, conf=0.88)
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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
- 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
- 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
- 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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