Evaluation of the Relative Bioavailability of Bosutinib Capsules Under Fed Condition and Estimation of Food Effect on Orally Administered Bosutinib Capsule

A PHASE 1, RANDOMIZED, OPEN-LABEL, 3-PERIOD, 4-SEQUENCE, CROSSOVER, SINGLE-DOSE STUDY TO COMPARE THE BIOAVAILABILITY OF ORALLY ADMINISTERED BOSUTINIB CAPSULES AND TO ESTIMATE THE EFFECT OF FOOD ON BOSUTINIB CAPSULE

This study is intended to estimate the bioavailability of a single 100 mg bosutinib capsules relative to four 25 mg capsules under fed condition in adult healthy participants and to estimate the effect of a high-fat, high-calorie meal on the bioavailability of a single 100 mg capsule of bosutinib relative to fasted condition in adults healthy participants. The comparisons will be performed using the pharmacokinetic parameters that define the rate and extend of absorption (Cmax, AUC). Statistical analyses will be performed after the administration of a single 100 mg dose under fed condition as the Reference treatment and the four 25 mg capsules as the Test treatment for the first comparison, and after administration of a single 100 mg dose under fasted condition as the Reference treatment and the 100 mg capsule under fed condition as the Test treatment for the second comparison.

Study Overview

• Status: Completed
• Conditions: Healthy Participants
• Intervention / Treatment: Drug: Bosutinib capsule; Drug: Bosutinib capsule; Drug: Bosutinib capsule; Drug: Bosutinib

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles-capitale, Région DE
    • Brussels, Bruxelles-capitale, Région DE, Belgium, B-1070
      • Pfizer Clinical Research Unit - Brussels

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Female participants of non-childbearing potential and/or male participants must be 18 to 55 years of age, inclusive, at the time of signing the informed consent document (ICD)
• participants who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination, vital signs which include BP and pulse rate measurement, clinical laboratory tests, and electrocardiogram (ECG).
• Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures

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 (eg, gastrectomy, cholecystectomy).
• History of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg,hepatitis B surface antigen (HBcAb) or hepatitis C antibody (HCVAb).

• 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:

  • estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) <90 mL/min/1.73 m2;
  • aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level >upper limit of normal (ULN);
  • 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;
  • Amylase and lipase level > ULN.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment B: Bosutinib four 25 mg capsule after meal; Bosutinib four 25 mg capsule taken after a high-fat and high-calorie breakfast for comparison 1	Drug: Bosutinib capsule; Bosutinib four 25 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high-calorie breakfast
Active Comparator: Treatment A: Bosutinib 100 mg capsule after meal (active comparator); Bosutinib 100 mg capsule taken after a high-fat and high-calorie breakfast for comparison 1	Drug: Bosutinib capsule; Bosutinib four 25 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high-calorie breakfast
Experimental: Treatment A: Bosutinib 100 mg capsule after meal (experimental); Bosutinib 100 mg capsule taken after a high-fat and high-calorie breakfast for comparison 2	Drug: Bosutinib capsule; Bosutinib four 25 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high calorie breakfast; Drug: Bosutinib capsule; Bosutinib 100 mg capsule taken after a high-fat and high-calorie breakfast
Active Comparator: Treatment C: Bosutinib 100 mg capsule after fasting; Bosutinib 100 mg capsule taken after an overnight fast of at least 10 hours for comparison 2	Drug: Bosutinib; Bosutinib 100 mg capsule taken after an overnight fast of at least 10 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Maximum Observed Plasma Concentration (Cmax) for Bosutinib	Cmax was the maximum observed plasma concentration. The geometric coefficient of variation was reported as percentage.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Time for Cmax (Tmax) of Bosutinib	Tmax was the time to reach maximum observed plasma concentration and was observed directly from data as time of the first occurrence.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Apparent Clearance After Oral Dose (CL/F) of 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.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Apparent Volume of Distribution After Oral Dose (Vz/F) of 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.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Terminal Elimination Half-Life (t1/2) of 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.	Predose (0 hour) and at 1, 2, 3, 4, 6, 8, 12, 24, 36, 48, 60, 72, 96, and 144 hours post bosutinib dose
Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)	Laboratory tests included hematology tests, chemistry tests, and urinalysis tests. Laboratory parameters with at least 1 occurrence meeting the pre-defined criteria are reported for this outcome measure.	On Days 4, 5, 7 of Periods 1 and 2 for all participants, on Period 3 Days 4, 5, 7 for participants who were assigned to treatment sequences A=>B=>C and B=>A=>C, and at early termination/discontinuation (if applicable)
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	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.	Post first dose on Period 1 Day 1 up to 28 days post the last dose of study intervention (up to a maximum of 75 days)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2022
• Primary Completion (Actual): June 25, 2022
• Study Completion (Actual): June 25, 2022

Study Registration Dates

• First Submitted: August 27, 2021
• First Submitted That Met QC Criteria: August 27, 2021
• First Posted (Actual): September 2, 2021

Study Record Updates

• Last Update Posted (Actual): September 20, 2024
• Last Update Submitted That Met QC Criteria: May 20, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Bioavailability; Bosutinib; Food Effect; Maximum Observed Plasma Concentration (Cmax); Area Under the Curve (AUC)
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Bosutinib
• Other Study ID Numbers: B1871062; 2021-004911-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No