Study to Collect Samples for MIST Analysis of Zibotentan and Bioavailability of Zibotentan and Dapagliflozin in Heatlhy Participants
- Conditions
- Chronic Kidney Disease
- Interventions
- Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)
- Registration Number
- NCT04991571
- Lead Sponsor
- AstraZeneca
- Brief Summary
The study will have 2 independent parts:
Part 1 of the study is intended to collect samples for Metabolites in Safety Testing (MIST) analysis after administration of multiple doses of zibotentan.
Part 2 of the study is designed to evaluate the relative bioavailability of zibotentan and dapagliflozin after dosing with two different fixed-dose combination (FDC) formulations and dosing with separate formulations of zibotentan and dapagliflozin.
- Detailed Description
Part 1 will be an open-label, non-randomised, single treatment period. A single treatment period during which participants will be resident at the study centre from 2 days before dosing (Day -2) until the morning of Day 6.
Part 2 will be an open-label, randomised, 3-period, 3-treatment, cross-over single dose study. Participants will be randomised to one of 3 treatment sequences and will receive 3 single-dose study interventions. Participants will be resident at the study centre from 2 days before dosing (Day -2) until Day 3 of the last treatment sequence.
Participants who were enrolled in Part 1 may not be enrolled in Part 2.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 27
For inclusion in the study participants should fulfil the following criteria:
- Participants with suitable veins for cannulation or repeated venipuncture.
- Females must have a negative pregnancy test at the Screening Visit and within 24 hours prior to dosing, must not be lactating and must be of non- childbearing potential
- Male participant must adhere to the contraception methods.
- Have a BMI between 18 and 29.9 kg/m^2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
- Provision of signed and dated, written informed consent prior to any study specific procedures.
Participants will not enter the study if any of the following exclusion criteria are fulfilled:
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History or presence of gastrointestinal, hepatic or renal disease or any important disease or disorder.
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Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study intervention.
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Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis.
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Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and Human immunodeficiency virus antibody.
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Abnormal vital signs. 6 History of drug abuse or alcohol abuse.
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History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity.
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Participants who are vegans or have medical dietary restrictions. 9. Participants tested positive for COVID-19 at the time of randomisation or have been previously hospitalised with COVID-19 infection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Part 2: Treatment Sequence BCA Zibotentan (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence CAB Zibotentan (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 1 Zibotentan (Treatment A) Participants will be administered with zibotentan once daily for 5 days. Part 2: Treatment Sequence ABC Zibotentan (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence ABC Dapagliflozin (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence ABC Zibotentan/Dapagliflozin - Formulation 1 (Treatment B) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence ABC Zibotentan/Dapagliflozin - Formulation 2 (Treatment C) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment A; Treatment B; Treatment C) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence BCA Dapagliflozin (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence BCA Zibotentan/Dapagliflozin - Formulation 1 (Treatment B) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence BCA Zibotentan/Dapagliflozin - Formulation 2 (Treatment C) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment B; Treatment C; Treatment A) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence CAB Dapagliflozin (Treatment A) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence CAB Zibotentan/Dapagliflozin - Formulation 1 (Treatment B) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods. Part 2: Treatment Sequence CAB Zibotentan/Dapagliflozin - Formulation 2 (Treatment C) Each participant will receive 3 single-dose treatments of zibotentan and dapagliflozin (Treatment C; Treatment A; Treatment B) in 3 treatment periods, separated by a washout period of at least 7 days between treatment periods.
- Primary Outcome Measures
Name Time Method Part 1: Metabolites in Safety Testing sampling Day 1 through Day 6 (pre-dose, 30 min; 1, 2, 4, 6, 8, 12 and 24 hours post dose) Plasma sample will be collected to understand the PK profiling of zibotentan metabolites and to meet the regulatory requirements.
Part 2: Maximum observed plasma drug concentration (Cmax) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Observed concentration at 24 hours post-dose (C24) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
- Secondary Outcome Measures
Name Time Method Part 2: Time to reach peak or maximum observed concentration (tmax) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Terminal rate constant (λz) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Half life associated with λz (t½λz) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 2: Volume of distribution at steady state following extravascular administration (Vz/F) Day 1 through Day 3 of each treatment period Relative bioavailability of zibotentan and dapagliflozin after dosing with two different FDC formulations and dosing with separate formulations of zibotentan and dapagliflozin will be evaluated.
Part 1 and Part 2: Number of adverse events and serious adverse events From Sceerning to Follow-up Visit approximately 40 days for Part 1 and 49 days for Part 2 Safety and tolerability of zibotentan and dapagliflozin will be studied.
Trial Locations
- Locations (1)
Research Site
🇺🇸Brooklyn, Maryland, United States