Study to Collect Samples for MIST Analysis of Zibotentan and Bioavailability of Zibotentan and Dapagliflozin in Heatlhy Participants

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1, Open-label Study With Two Independent Parts: Collecting Samples for Metabolites in Safety Testing Analysis of Zibotentan After Repeated Administration (Part 1); and a Randomised, Cross-over, Three Period, Three-treatment, Single Dose Study to Assess the Relative Bioavailability of Different Formulations of Zibotentan and Dapagliflozin (Part 2) in Healthy Adult Participants

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Zibotentan (Treatment A)
* Drug: Dapagliflozin (Treatment A)
* Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)
* Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: Participants will not enter the study if any of the following exclusion criteria are fulfilled: History or presence of gastrointestinal, hepatic or renal disease or any important disease or disorder. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of study intervention. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis. Any positive result on screening for serum hepatitis B surface antigen, hepatitis C antibody, and Human immunodeficiency virus antibody. Abnormal vital signs. 6 History of drug abuse or alcohol abuse. 7. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity. 8. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1<br>Participants will be administered with zibotentan once daily for 5 days. | Drug: Zibotentan (Treatment A)<br>* Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.<br>|
| Experimental: Part 2: Treatment Sequence ABC<br>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)<br>* Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.<br>Drug: Dapagliflozin (Treatment A)<br>* Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>|
| Experimental: Part 2: Treatment Sequence BCA<br>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)<br>* Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.<br>Drug: Dapagliflozin (Treatment A)<br>* Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>|
| Experimental: Part 2: Treatment Sequence CAB<br>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)<br>* Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.<br>Drug: Dapagliflozin (Treatment A)<br>* Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 1 (Treatment B)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>Drug: Zibotentan/Dapagliflozin - Formulation 2 (Treatment C)<br>* Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Metabolites in Safety Testing sampling | Plasma sample will be collected to understand the PK profiling of zibotentan metabolites and to meet the regulatory requirements. | Day 1 through Day 6 (pre-dose, 30 min; 1, 2, 4, 6, 8, 12 and 24 hours post dose) | 
| Part 2: Area under plasma concentration time curve from zero to infinity (AUCinf) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Maximum observed plasma drug concentration (Cmax) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Observed concentration at 24 hours post-dose (C24) | 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. | Day 1 through Day 3 of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Time to reach peak or maximum observed concentration (tmax) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Terminal rate constant (λz) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Half life associated with λz (t½λz) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 2: Volume of distribution at steady state following extravascular administration (Vz/F) | 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. | Day 1 through Day 3 of each treatment period | 
| Part 1 and Part 2: Number of adverse events and serious adverse events | Safety and tolerability of zibotentan and dapagliflozin will be studied. | From Sceerning to Follow-up Visit approximately 40 days for Part 1 and 49 days for Part 2 |