Study to Collect Samples for MIST Analysis of Zibotentan and Bioavailability of Zibotentan and Dapagliflozin in Heatlhy Participants
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1 Participants will be administered with zibotentan once daily for 5 days. |
Drug: Zibotentan (Treatment A)
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
|
| Experimental: Part 2: Treatment Sequence ABC 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. |
Drug: Zibotentan (Treatment A)
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
Drug: Dapagliflozin (Treatment A)
Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
|
| Experimental: Part 2: Treatment Sequence BCA 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. |
Drug: Zibotentan (Treatment A)
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
Drug: Dapagliflozin (Treatment A)
Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
|
| Experimental: Part 2: Treatment Sequence CAB 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. |
Drug: Zibotentan (Treatment A)
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
Drug: Dapagliflozin (Treatment A)
Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
|
Outcome Measures
Primary Outcome Measures
- 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: 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: 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: 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
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
For inclusion in the study participants should fulfil the following criteria:
-
Participants with suitable veins for cannulation or repeated venipuncture.
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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
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Male participant must adhere to the contraception methods.
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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.
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Provision of signed and dated, written informed consent prior to any study specific procedures.
Exclusion Criteria:
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Brooklyn | Maryland | United States | 21225 |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D4325C00003