Pharmacokinetic Study in Healthy Participants
Conditions
Brief summary
The purpose of the study is to compare the blood levels of dasatinib in healthy participants who received tablet formulation with those of healthy participants who received liquid and tablet-dispersed formulations of the drug.
Interventions
DRUGDasatinib as tablets
2 50-mg tablets plus 240 mL noncarbonated, nonrefrigerated water. Oral, single dose, 1 day
DRUGDasatinib as liquid
100 mg administered as 10 mL of liquid drug (10 mg/mL) plus 230 mL noncarbonated, nonrefrigerated water. Oral, single dose, 1 day
DRUGDasatinib as dispersed tablets
2 50-mg dispersed tablets in 30 mL of 100% orange juice followed by 15 mL of orange juice plus 195 mL noncarbonated, nonrefrigerated water. Liquid (oral solution), single dose, 1 day.
Sponsors
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Healthy participants, defined as having no clinically relevant deviation from normal in medical history, physical examination, electrocardiogram (ECG) findings, and clinical laboratory tests findings. * Body mass index of 18 to 32 kg/m\^2, inclusive * Age from 18 to 55 years * Men and women who were not of childbearing potential (ie, who were postmenopausal or surgically sterile) * All women must have had a negative serum or urine pregnancy test result(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) at screening and within 24 hours prior to dosing with study drug * Women must not have been breastfeeding * Sexually active fertile men with female partners of childbearing potential were required to abide by the requirement to use effective birth control for the entire study and for 90 days after the date of last treatment * Men must have agreed not to donate sperm for the entire study and for 90 days after the day of last study treatment * Participants must have agreed not to make blood donations, including red blood cells, plasma, platelets, or whole blood, for the entire study and for 8 weeks after the day of last study treatment Key
Exclusion criteria
* Any significant acute or chronic medical illness * Current or recent (within 3 months of study drug administration) disease of the gastrointestinal (GI) tract that may impact drug absorption and may affect pharmacokinetics of the study drugs or any GI tract surgery that may impact drug absorption * Any major surgery, as determined by the investigator, within 4 weeks of dosing in Period 1 * Blood transfusion within 4 weeks of study drug administration * Donation of \>400 mL of blood within 8 weeks prior to study dosing or donation of plasma within 4 weeks prior to study dosing * Inability to tolerate oral medication * Inability to tolerate orange juice * Inability to undergo venipuncture and/or tolerate venous access * Use of tobacco or nicotine-containing products within 6 months prior to check-in, or positive nicotine test at screening and/or check-in * Consumption of more than 3 cups of coffee or other caffeine-containing products a day, or 5 cups of tea a day * Recent (within 6 months of study drug administration) drug or alcohol abuse * Positive blood screen for hepatitis C antibody; hepatitis B surface antigen; and HIV-1, HIV-2, or HIV antibody * History of any significant drug allergy or asthma * Evidence of organ dysfunction or any clinically relevant deviation from normal in physical examination, ECG findings, vital signs, or clinical laboratory test findings. * Any of the following on 12-lead ECG prior to study drug administration, confirmed by repeat ECG: * PR ≥210 ms * QRS ≥120 ms * QT ≥500 ms * QTcF ≥450 ms
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of Dasatinib | Days 1-2, Days 5-6, and Days 9-10 | Single-dose pharmacokinetic parameters, including Cmax, were derived using noncompartmental methods from plasma dasatinib concentration-time data. |
| Area Under the Plasma Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration (AUC[0-T])of Dasatinib | Days 1-2, Days 5-6, and Days 9-10 | Single-dose pharmacokinetic, such as AUC(0-T),parameters were derived using noncompartmental methods from plasma dasatinib concentration-time data. |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-INF]) of Dasatinib | Days 1-2, Days 5-6, and Days 9-10 | Single-dose pharmacokinetic parameters, such as AUC(0-INF) were derived using noncompartmental methods from plasma dasatinib concentration-time data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Day -1, Screening, and Days 1, 5, 9 and 10 (at study discharge) | Blood pressure and heart rate were measured after the participant had been seated quietly for at least 5 minutes. ECG findings were recorded after the participant had been supine for at least 5 minutes. Clinically significant as reported by principal investigator. |
| Time of Maximum Observed Plasma Concentration (Tmax) of Dasatinib | Days 1-2, Days 5-6, and Days 9-10 | Single-dose pharmacokinetic parameters, such as Tmax, were derived using noncompartmental methods from plasma dasatinib concentration-time data. |
| Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Day -1, Screening, and Day 9 of current treatment regimen | Criteria for normal: bilirubin (0.2 to 1.3 mg/dL); lactate dehydrogenase (101 to 227 U/L); eosinophils (0.06 to 0.87\*103 c/μL); erythrocytes (4.2 to 5.8\*10\^6 c/μL). Participants were required to fast for a minimum of 4 hours prior to the collection of specimens for clinical laboratory tests at screening and for at least 8 hours prior to collection on Day -1. Marked abnormalities were reported for the treatment regiment that participants received just prior to clinical laboratory testing. |
| Half-life of Dasatinib | Days 1-2, Days 5-6, and Days 9-10 | — |
| Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | Continually from enrollment through Day 9 and at study discharge on Day 10 | An AE is any new untoward medical occurrence or worsening of a preexisting medical condition in a patient or clinical investigation participant who has received an investigational (medicinal) product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is an untoward medical event that at any dose results in death, persistent or significant disability/incapacity; is life-threatening or a congenital anomaly/birth defect; or requires or prolongs hospitalization; is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention. |
Countries
United States
Participant flow
Pre-assignment details
A total of 141 participants were enrolled, of which 78 were randomized to and received treatment in 1 of 6 sequences(ABC, ACB, BCA, BAC, CAB, or CBA), administered over 3 1-day treatment periods (Days 1, 5, and 9), with treatment changing to next in the sequence at start of each new period. A 3-day washout period followed treatment periods 1 and 2.
Participants by arm
| Arm | Count |
|---|---|
| All Treated | 78 |
| Total | 78 |
Baseline characteristics
| Characteristic | All Treated |
|---|---|
| Age Continuous | 36.5 years STANDARD_DEVIATION 8.75 |
| Age, Customized Younger than 65 years | 78 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 39 Participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 39 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 71 Participants |
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 | 42 / 78 | 44 / 77 | 35 / 77 |
| serious Total, serious adverse events | 0 / 78 | 0 / 77 | 0 / 77 |
Outcome results
Primary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-INF]) of Dasatinib
Single-dose pharmacokinetic parameters, such as AUC(0-INF) were derived using noncompartmental methods from plasma dasatinib concentration-time data.
Time frame: Days 1-2, Days 5-6, and Days 9-10
Population: All participants who received at least 1 dose of any study drug and had pharmacokinetic data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-INF]) of Dasatinib | 429 ng*h/mL | Geometric Coefficient of Variation 39 |
| Dasatinib, 100 mg as Liquid + Water | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-INF]) of Dasatinib | 338 ng*h/mL | Geometric Coefficient of Variation 43 |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC[0-INF]) of Dasatinib | 353 ng*h/mL | Geometric Coefficient of Variation 41 |
Primary
Area Under the Plasma Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration (AUC[0-T])of Dasatinib
Single-dose pharmacokinetic, such as AUC(0-T),parameters were derived using noncompartmental methods from plasma dasatinib concentration-time data.
Time frame: Days 1-2, Days 5-6, and Days 9-10
Population: All participants who received at least 1 dose of any study drug and had pharmacokinetic data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Area Under the Plasma Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration (AUC[0-T])of Dasatinib | 374 ng*h/mL | Geometric Coefficient of Variation 45 |
| Dasatinib, 100 mg as Liquid + Water | Area Under the Plasma Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration (AUC[0-T])of Dasatinib | 327 ng*h/mL | Geometric Coefficient of Variation 44 |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Area Under the Plasma Concentration-time Curve From Zero to the Last Time of the Last Quantifiable Concentration (AUC[0-T])of Dasatinib | 342 ng*h/mL | Geometric Coefficient of Variation 42 |
Primary
Maximum Observed Concentration (Cmax) of Dasatinib
Single-dose pharmacokinetic parameters, including Cmax, were derived using noncompartmental methods from plasma dasatinib concentration-time data.
Time frame: Days 1-2, Days 5-6, and Days 9-10
Population: All participants who received at least 1 dose of any study drug and had pharmacokinetic data available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Maximum Observed Concentration (Cmax) of Dasatinib | 114 ng/mL | Geometric Coefficient of Variation 51 |
| Dasatinib, 100 mg as Liquid + Water | Maximum Observed Concentration (Cmax) of Dasatinib | 106 ng/mL | Geometric Coefficient of Variation 53 |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Maximum Observed Concentration (Cmax) of Dasatinib | 110 ng/mL | Geometric Coefficient of Variation 50 |
Secondary
Half-life of Dasatinib
Time frame: Days 1-2, Days 5-6, and Days 9-10
Population: All participants who received at least 1 dose of any study drug and had pharmacokinetic data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Half-life of Dasatinib | 4.96 Hours | Standard Deviation 1.31 |
| Dasatinib, 100 mg as Liquid + Water | Half-life of Dasatinib | 4.82 Hours | Standard Deviation 1.17 |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Half-life of Dasatinib | 4.91 Hours | Standard Deviation 1.25 |
Secondary
Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE)
An AE is any new untoward medical occurrence or worsening of a preexisting medical condition in a patient or clinical investigation participant who has received an investigational (medicinal) product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. An SAE is an untoward medical event that at any dose results in death, persistent or significant disability/incapacity; is life-threatening or a congenital anomaly/birth defect; or requires or prolongs hospitalization; is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention.
Time frame: Continually from enrollment through Day 9 and at study discharge on Day 10
Population: All participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 AE | 42 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 treatment-related AE | 39 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | Discontinuation due to AEs | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 SAE | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 SAE | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 AE | 44 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | Discontinuation due to AEs | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 treatment-related AE | 43 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 SAE | 0 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 treatment-related AE | 34 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | Discontinuation due to AEs | 0 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With at Least 1 Adverse Event (AE), With at Least 1 Treatment-related AE, Who Discontinued Due to AEs, and With at Least 1 Serious Adverse Event (SAE) | At least 1 AE | 35 Participants |
Secondary
Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings
Blood pressure and heart rate were measured after the participant had been seated quietly for at least 5 minutes. ECG findings were recorded after the participant had been supine for at least 5 minutes. Clinically significant as reported by principal investigator.
Time frame: Day -1, Screening, and Days 1, 5, 9 and 10 (at study discharge)
Population: All participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Respiratory rate | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Temperature | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Systolic blood pressure | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Diastolic blood pressure | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | Heart rate | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | QT and QTc Intervals | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Clinically Significant Changes in Vital Signs or Electrocardiogram (ECG) Findings | QRS and PR intervals | 0 Participants |
Secondary
Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests
Criteria for normal: bilirubin (0.2 to 1.3 mg/dL); lactate dehydrogenase (101 to 227 U/L); eosinophils (0.06 to 0.87\*103 c/μL); erythrocytes (4.2 to 5.8\*10\^6 c/μL). Participants were required to fast for a minimum of 4 hours prior to the collection of specimens for clinical laboratory tests at screening and for at least 8 hours prior to collection on Day -1. Marked abnormalities were reported for the treatment regiment that participants received just prior to clinical laboratory testing.
Time frame: Day -1, Screening, and Day 9 of current treatment regimen
Population: All participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated bilirubin | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated eosinophils | 0 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood in urine (2+) | 1 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Low erythrocytes | 1 Participants |
| Dasatinib, 100 mg as Tablets + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated lactate dehydrogenase | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood in urine (2+) | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated bilirubin | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated lactate dehydrogenase | 1 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated eosinophils | 0 Participants |
| Dasatinib, 100 mg as Liquid + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Low erythrocytes | 0 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Low erythrocytes | 0 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated eosinophils | 1 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated bilirubin | 1 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Blood in urine (2+) | 0 Participants |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Number of Participants With Marked Abnormalities in Results of Clinical Laboratory Tests | Elevated lactate dehydrogenase | 0 Participants |
Secondary
Time of Maximum Observed Plasma Concentration (Tmax) of Dasatinib
Single-dose pharmacokinetic parameters, such as Tmax, were derived using noncompartmental methods from plasma dasatinib concentration-time data.
Time frame: Days 1-2, Days 5-6, and Days 9-10
Population: All participants who received at least 1 dose of any study drug and had pharmacokinetic data available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dasatinib, 100 mg as Tablets + Water | Time of Maximum Observed Plasma Concentration (Tmax) of Dasatinib | 1.00 Hours |
| Dasatinib, 100 mg as Liquid + Water | Time of Maximum Observed Plasma Concentration (Tmax) of Dasatinib | 0.53 Hours |
| Dasatinib, 100 mg as Tablets in Orange Juice + Water | Time of Maximum Observed Plasma Concentration (Tmax) of Dasatinib | 0.50 Hours |