Bioavailability of Apixaban Crushed Tablet

Relative Bioavailability of Crushed Apixaban Tablets Administered With Water or Apple Sauce Compared With Intact Tablet in Healthy Subjects

The purpose of this study is to determine whether the bioavailability of apixaban crushed tablets suspended in water or mixed with applesauce is similar to the bioavailability of apixaban whole tablets administered orally.

Study Overview

• Status: Completed
• Conditions: Thrombosis
• Intervention / Treatment: Drug: Apixaban

Detailed Description

This study will investigate the bioavailability of apixaban administered as crushed tablets suspended in water and as crushed tablets mixed with applesauce compared with that of whole tablets. The study results may allow enhancement of the apixaban label to include alternative methods of apixaban administration, which may be of benefit to patients who have difficulty swallowing.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Healthy participants as determined by no clinically significant deviation from normal in findings of medical history, physical examination, electrocardiograms, vital signs, and clinical laboratory tests.
• Women of childbearing potential allowed. Must be following highly effective methods of contraception

Exclusion Criteria:

• Any significant acute or chronic medical illness
• History of significant head injury within the last 2 years, including individuals with base of skull fractures
• Any major surgery within 4 weeks of study drug administration or anticipated within 2 weeks after completion of the study
• Any gastrointestinal (GI) surgery or GI disease that could impact absorption of study drug
• History of Gilbert's Syndrome
• Inability to tolerate oral medication
• Inability to be venipunctured and/or tolerate venous access
• Use of tobacco- or nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patches, nicotine lozenges, or nicotine gum) within 6 months prior to study drug administration

• Any laboratory test results outside of the range of normal, confirmed by repeat results of:

  • Platelet count <150,000 cells/µL
  • Activated partial thromboplastin time >upper limit of normal (ULN)
  • International normalized ratio >ULN
  • Alanine aminotransferase >ULN
  • Aspartate aminotransferase >ULN
  • Total bilirubin >ULN
  • Serum creatinine ≥1.5 mg/dL
  • Hemoglobin <lower limit of normal (LLN)
  • Hematocrit <LLN

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apixaban, 10 mg (whole tablets); Participants received a single dose of apixaban, 10 mg, given orally as 2 5-mg whole commercial tablets (reference)	Drug: Apixaban; Other Names: Eliquis®
Experimental: Apixaban, 10 mg (crushed and suspended in water); Participants received a single dose of apixaban, 10 mg, given by mouth as 2 5-mg whole commercial tablets crushed and suspended in 30 mL of water	Drug: Apixaban; Other Names: Eliquis®
Experimental: Apixaban, 10 mg (crushed and mixed with applesauce); Participants received a single dose of 10 mg, given by mouth as 2 5-mg apixaban commercial tablets crushed and mixed with 30 g of applesauce	Drug: Apixaban; Other Names: Eliquis®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban	Maximum observed plasma concentration (Cmax) measured in nanograms per milliliter (ng/mL)	Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60 and 72 hours post dose
Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban	Area Under the Plasma Concentration-time Curve (AUC) From Time of Zero Extrapolated to Infinite Time (INF) [AUC (INF)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL)	Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose
Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] of Apixaban	Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to the Last Quantifiable Concentration [AUC (0-T)] is measured as nanograms multiplied by hours per milliliter (ng*h/mL)	Days 1, 5, and 9 predose and 0.5, 1, 2, 3, 4, 5, 6, 9, 12, 24, 36, 48, 60, and 72 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion	Adverse Event (AE) = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Serious Adverse Event (SAE)= a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.	Randomization to May 2014; approximately 6 weeks
Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban	Time of maximum observed plasma concentration (Tmax) measured in hours (h)	Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose
Terminal Plasma Half-life (T-HALF) of Apixaban	Terminal plasma half-life (T-HALF) was derived from plasma concentration versus time data. T-HALF was the time required for one half of the total amount of administered drug to be eliminated from the body.	Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose
Relative Bioavailability (Frel) of Apixaban	Frel is calculated using the treatment ratio of AUC(INF) where the denominator is the AUC(INF) of the reference therapy, 10mg of Apixaban (whole tablet).	Days 1, 5 and 9 pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 9, 12 24, 36, 48, 60 and 72 hrs post dose

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Song Y, Chang M, Suzuki A, Frost RJ, Kelly A, LaCreta F, Frost C. Evaluation of Crushed Tablet for Oral Administration and the Effect of Food on Apixaban Pharmacokinetics in Healthy Adults. Clin Ther. 2016 Jul;38(7):1674-1685.e1. doi: 10.1016/j.clinthera.2016.05.004. Epub 2016 Jun 10.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: March 28, 2014
• First Submitted That Met QC Criteria: March 28, 2014
• First Posted (Estimate): April 1, 2014

Study Record Updates

• Last Update Posted (Estimate): March 3, 2016
• Last Update Submitted That Met QC Criteria: February 29, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thrombosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: CV185-292