Thrombosis
Conditions
Brief summary
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.
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.
Interventions
DRUGApixaban
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | 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 | Maximum observed plasma concentration (Cmax) measured in nanograms per milliliter (ng/mL) |
| Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | 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 | 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) |
| 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 | 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 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Randomization to May 2014; approximately 6 weeks | 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. |
| Relative Bioavailability (Frel) of Apixaban | 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 | 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). |
| Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | 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 | Time of maximum observed plasma concentration (Tmax) measured in hours (h) |
| Terminal Plasma Half-life (T-HALF) of Apixaban | 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) 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. |
Participant flow
Pre-assignment details
69 participants enrolled, 33 participants randomized. 36 participants were enrolled but not randomized. Reasons for non-randomization include 30 participants no longer met study criteria, 4 participants withdrew consent, 2 participants were not needed for the study.
Participants by arm
| Arm | Count |
|---|---|
| Apixaban, 10 mg (Whole Tablets) This was a 3-period, 3-treatment crossover study. Each participant received (orally) a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and suspended in 30 mL water and a single-dose of apixaban 10 mg (two 5-mg tablets) crushed and mixed with 30 g applesauce according to a randomization schedule. Each participant underwent a washout of at least 4 days before receiving the next scheduled treatment. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Apixaban, 10 mg (Whole Tablets) |
|---|---|
| Age, Continuous | 32.3 years STANDARD_DEVIATION 7.35 |
| Body Mass Index (BMI) | 26.14 kilograms per meter^2 STANDARD_DEVIATION 2.166 |
| Height | 172.13 centimeters STANDARD_DEVIATION 8.322 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 26 Participants |
| Weight | 77.40 kilograms STANDARD_DEVIATION 7.933 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 32 | 0 / 33 | 0 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 33 | 0 / 32 |
Outcome results
Primary
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)
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | 2461 ng*h/mL |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | 2528 ng*h/mL |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Adjusted Geometric Mean of Area Under the Plasma Concentration-time Curve (AUC) From Time Zero Extrapolated to Infinite Time [AUC(INF)] of Apixaban | 2055 ng*h/mL |
Comparison: Apixaban, 10 mg (crushed and suspended in water) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.981, 1.076]
Comparison: Apixaban, 10 mg (crushed and mixed with applesauce) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.797, 0.875]
Primary
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)
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | 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 | 2423 ng*h/mL |
| Apixaban, 10 mg (Crushed and Suspended in Water) | 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 | 2488 ng*h/mL |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | 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 | 2015 ng*h/mL |
Comparison: Apixaban, 10 mg (crushed and suspended in water) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.981, 1.075]
Comparison: Apixaban, 10 mg (crushed and mixed with applesauce) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.794, 0.871]
Primary
Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban
Maximum observed plasma concentration (Cmax) measured in nanograms per milliliter (ng/mL)
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | 236 ng/mL |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | 249 ng/mL |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Adjusted Geometric Mean of Maximum Observed Plasma Concentration (Cmax) of Apixaban | 186 ng/mL |
Comparison: Apixaban, 10 mg (crushed and suspended in water) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.994, 1.118]
Comparison: Apixaban, 10 mg (crushed and mixed with applesauce) vs. Apixaban, 10 mg (whole tablets)90% CI: [0.741, 0.839]
Secondary
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.
Time frame: Randomization to May 2014; approximately 6 weeks
Population: All randomized and treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Deaths | 0 participants |
| Apixaban, 10 mg (Whole Tablets) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | SAEs | 0 participants |
| Apixaban, 10 mg (Whole Tablets) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Drug-related AEs | 0 participants |
| Apixaban, 10 mg (Whole Tablets) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Discontinuation due to AE | 0 participants |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Discontinuation due to AE | 1 participants |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Deaths | 0 participants |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Drug-related AEs | 1 participants |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | SAEs | 0 participants |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Discontinuation due to AE | 0 participants |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | SAEs | 0 participants |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Drug-related AEs | 0 participants |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Number of Participants With Serious Adverse Events, Death, or Discontinuation Due to Adverse Events by Study Completion | Deaths | 0 participants |
Secondary
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).
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Relative Bioavailability (Frel) of Apixaban | 1.03 ratio | Geometric Coefficient of Variation 24 |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Relative Bioavailability (Frel) of Apixaban | 0.836 ratio | Geometric Coefficient of Variation 20 |
Secondary
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.
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Terminal Plasma Half-life (T-HALF) of Apixaban | 12.4 hours | Standard Deviation 5.39 |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Terminal Plasma Half-life (T-HALF) of Apixaban | 12.2 hours | Standard Deviation 5.19 |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Terminal Plasma Half-life (T-HALF) of Apixaban | 12.5 hours | Standard Deviation 5.05 |
Secondary
Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban
Time of maximum observed plasma concentration (Tmax) measured in hours (h)
Time frame: 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
Population: All evaluable pharmacokinetic (PK) participants who were treated with apixaban
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Apixaban, 10 mg (Whole Tablets) | Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | 2.00 hours |
| Apixaban, 10 mg (Crushed and Suspended in Water) | Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | 2.00 hours |
| Apixaban, 10 mg (Crushed and Mixed With Applesauce) | Time of Maximum Observed Plasma Concentration (Tmax) of Apixaban | 2.00 hours |