Healthy Participants
Conditions
Keywords
Bioavailability, bosutinib, Maximum Observed Plasma Concentration (Cmax), Area Under the Curve (AUC)
Brief summary
This study is intended to estimate the relative bioavailability of a single 500 mg dose of bosutinib when administered as capsule contents mixed with applesauce or yogurt to intact capsules under fed condition in adult healthy participants. The comparisons will be performed using the pharmacokinetic parameters that define the rate and extent of absorption, those are Cmax and AUC. Statistical analyses will be performed comparing these parameters calculated after administration of a single 500 mg dose with the intact capsule formulation (100 mg x 5) as the Reference treatment and the capsule contents mixed with applesauce or yogurt (100 mg x 5) as the Test treatments.
Interventions
500 mg dose of bosutinib capsule contents mixed with applesauce
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
A Phase 1, open-label, randomized, single dose, 3-period, 6-sequence, crossover study in healthy participants
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Female participants of non childbearing potential and/or male participants must be 18 to 54 years of age, inclusive, at the time of signing the informed consent document (ICD). * Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, dermatological, or allergic disease. * Any condition possibly affecting drug absorption. * Participants with ANY of the following abnormalities in clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat test, if deemed necessary: 1. estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\]) \< 90 mL/min/1.73 m2; 2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level \> upper limit of normal (ULN); 3. Serum (total and direct) bilirubin level \> ULN; participants with a history of Gilbert's syndrome may have direct bilirubin measured and would be eligible for this study provided the direct bilirubin level is \<= ULN; 4. Amylase and lipase levels \> ULN.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | AUCinf was calculated as \[AUClast+(Clast\*/kel)\], where AUClast is the area under the plasma concentration-time profile from time 0 to the time of the Clast, Clast is the last quantifiable concentration, Clast\* is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The geometric coefficient of variation was reported as percentage. |
| Maximum Observed Plasma Concentration (Cmax) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | Cmax was the maximum observed plasma concentration. The geometric coefficient of variation was reported as percentage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Clearance After Oral Dose (CL/F) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | CL/F was the apparent clearance after oral dose and was determined as dose/AUCinf. The geometric coefficient of variation was reported as percentage. |
| Apparent Volume of Distribution After Oral Dose (Vz/F) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | Vz/F was the apparent volume of distribution after oral dose. It was determined as dose/(AUCinf × kel), where kel was the terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration time curve. The geometric coefficient of variation was reported as percentage. |
| Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | AUClast was the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. Linear/Log trapezoidal method was used to determine AUClast. The geometric coefficient of variation was reported as percentage. |
| Number of Participants With Laboratory Abnormalities | Post first dose and up to Day 7 in Period 3, or at early termination/discontinuation. | Laboratory tests included hematology tests, chemistry tests, and urinalysis tests. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Up to 12 weeks | TEAEs are those with initial onset or that worsen in severity after the first dose of the study medication. All AEs in the table below were TEAEs. An SAE is any untoward medical occurrence at any dose that: results in death; is life threatening (immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); results in congenital anomaly/birth defect; or that is considered to be an important medical event. Severe AEs were defined as AEs that interfered significantly with participant's usual function. Both SAEs and severe AEs were according to the investigator's assessment. |
| Terminal Phase Half-life (t½ ) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | t½ was the terminal elimination plasma half-life. It was determined as Loge(2)/kel, where kel was the terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for Bosutinib | Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose | Tmax was the time to reach maximum observed plasma concentration and was observed directly from data as time of the first occurrence. |
Countries
Belgium
Participant flow
Pre-assignment details
A total of 18 participants were assigned to the study intervention, 16 of whom received all the 3 randomized treatment by sequence and completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. | 18 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Period 1 | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Period 2 | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 32.0 years |
| Age, Customized 18-25 years | 3 Participants |
| Age, Customized 26-35 years | 8 Participants |
| Age, Customized 36-45 years | 5 Participants |
| Age, Customized Older than 45 years | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 18 Participants |
| Race/Ethnicity, Customized White | 18 Participants |
| Sex: Female, Male Female | NA Participants |
| Sex: Female, Male Male | NA Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 11 / 16 | 14 / 17 | 15 / 18 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 | 0 / 18 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Bosutinib
AUCinf was calculated as \[AUClast+(Clast\*/kel)\], where AUClast is the area under the plasma concentration-time profile from time 0 to the time of the Clast, Clast is the last quantifiable concentration, Clast\* is the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. The geometric coefficient of variation was reported as percentage.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib pharmacokinetic (PK) parameter contributing to the summary statistics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Bosutinib | 3312 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 28 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Bosutinib | 3205 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 23 |
| Bosutinib 500 mg Intact Capsule | Area Under the Concentration-time Curve From Time 0 to Infinity (AUCinf) for Bosutinib | 3161 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 32 |
Comparison: Natural logarithm-transformed bosutinib AUCinf was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + applesauce 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% confidence intervals (CIs) were obtained from the model.90% CI: [97.76, 115.53]
Comparison: Natural logarithm-transformed bosutinib AUCinf was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + yogurt 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% CIs were obtained from the model.90% CI: [93.97, 110.56]
Primary
Maximum Observed Plasma Concentration (Cmax) for Bosutinib
Cmax was the maximum observed plasma concentration. The geometric coefficient of variation was reported as percentage.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Maximum Observed Plasma Concentration (Cmax) for Bosutinib | 126.5 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Maximum Observed Plasma Concentration (Cmax) for Bosutinib | 126.1 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 27 |
| Bosutinib 500 mg Intact Capsule | Maximum Observed Plasma Concentration (Cmax) for Bosutinib | 132.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 33 |
Comparison: Natural logarithm-transformed bosutinib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + applesauce 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% CIs were obtained from the model.90% CI: [86.37, 108.53]
Comparison: Natural logarithm-transformed bosutinib Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + yogurt 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% CIs were obtained from the model.90% CI: [85.34, 106.61]
Secondary
Apparent Clearance After Oral Dose (CL/F) for Bosutinib
CL/F was the apparent clearance after oral dose and was determined as dose/AUCinf. The geometric coefficient of variation was reported as percentage.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Apparent Clearance After Oral Dose (CL/F) for Bosutinib | 151.0 liter/hour | Geometric Coefficient of Variation 28 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Apparent Clearance After Oral Dose (CL/F) for Bosutinib | 156.0 liter/hour | Geometric Coefficient of Variation 23 |
| Bosutinib 500 mg Intact Capsule | Apparent Clearance After Oral Dose (CL/F) for Bosutinib | 158.1 liter/hour | Geometric Coefficient of Variation 32 |
Secondary
Apparent Volume of Distribution After Oral Dose (Vz/F) for Bosutinib
Vz/F was the apparent volume of distribution after oral dose. It was determined as dose/(AUCinf × kel), where kel was the terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration time curve. The geometric coefficient of variation was reported as percentage.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Apparent Volume of Distribution After Oral Dose (Vz/F) for Bosutinib | 7903 liter | Geometric Coefficient of Variation 31 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Apparent Volume of Distribution After Oral Dose (Vz/F) for Bosutinib | 8106 liter | Geometric Coefficient of Variation 28 |
| Bosutinib 500 mg Intact Capsule | Apparent Volume of Distribution After Oral Dose (Vz/F) for Bosutinib | 8145 liter | Geometric Coefficient of Variation 41 |
Secondary
Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Bosutinib
AUClast was the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration. Linear/Log trapezoidal method was used to determine AUClast. The geometric coefficient of variation was reported as percentage.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Bosutinib | 3150 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 28 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Bosutinib | 3055 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 23 |
| Bosutinib 500 mg Intact Capsule | Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Bosutinib | 3009 nanogram•hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 33 |
Comparison: Natural logarithm-transformed bosutinib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + applesauce 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% CIs were obtained from the model.90% CI: [97.54, 115.68]
Comparison: Natural logarithm-transformed bosutinib AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Bosutinib 500 mg capsule contents + yogurt 45 mL \[Test\] - Bosutinib 500 mg intact capsule \[Reference\]) and corresponding 90% CIs were obtained from the model.90% CI: [93.95, 110.91]
Secondary
Number of Participants With Laboratory Abnormalities
Laboratory tests included hematology tests, chemistry tests, and urinalysis tests.
Time frame: Post first dose and up to Day 7 in Period 3, or at early termination/discontinuation.
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Number of Participants With Laboratory Abnormalities | 8 Participants |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Number of Participants With Laboratory Abnormalities | 11 Participants |
| Bosutinib 500 mg Intact Capsule | Number of Participants With Laboratory Abnormalities | 11 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs)
TEAEs are those with initial onset or that worsen in severity after the first dose of the study medication. All AEs in the table below were TEAEs. An SAE is any untoward medical occurrence at any dose that: results in death; is life threatening (immediate risk of death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); results in congenital anomaly/birth defect; or that is considered to be an important medical event. Severe AEs were defined as AEs that interfered significantly with participant's usual function. Both SAEs and severe AEs were according to the investigator's assessment.
Time frame: Up to 12 weeks
Population: All participants randomly assigned to study intervention and who took at least 1 dose of study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with TEAEs | 11 Participants |
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with severe AEs | 0 Participants |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with TEAEs | 14 Participants |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with severe AEs | 0 Participants |
| Bosutinib 500 mg Intact Capsule | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with TEAEs | 15 Participants |
| Bosutinib 500 mg Intact Capsule | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with severe AEs | 0 Participants |
| Bosutinib 500 mg Intact Capsule | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Severe Adverse Events (AEs), and Serious Adverse Events (SAEs) | Participants with SAEs | 0 Participants |
Secondary
Terminal Phase Half-life (t½ ) for Bosutinib
t½ was the terminal elimination plasma half-life. It was determined as Loge(2)/kel, where kel was the terminal elimination phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Terminal Phase Half-life (t½ ) for Bosutinib | 36.46 hour | Standard Deviation 3.7067 |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Terminal Phase Half-life (t½ ) for Bosutinib | 36.30 hour | Standard Deviation 4.6893 |
| Bosutinib 500 mg Intact Capsule | Terminal Phase Half-life (t½ ) for Bosutinib | 36.02 hour | Standard Deviation 4.9889 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Bosutinib
Tmax was the time to reach maximum observed plasma concentration and was observed directly from data as time of the first occurrence.
Time frame: Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Population: Total number of participants received treatment and had bosutinib PK parameter contributing to the summary statistics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib 500 mg Capsule Contents + Applesauce 45 mL | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Bosutinib | 6.00 hour |
| Bosutinib 500 mg Capsule Contents + Yogurt 45 mL | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Bosutinib | 6.00 hour |
| Bosutinib 500 mg Intact Capsule | Time to Reach Maximum Observed Plasma Concentration (Tmax) for Bosutinib | 6.00 hour |