Chronic Kidney Disease
Conditions
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.
Interventions
DRUGZibotentan (Treatment A)
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
DRUGDapagliflozin (Treatment A)
Dapagliflozin tablet will be administered orally as single dose in Part 2.
DRUGZibotentan/Dapagliflozin - Formulation 1 (Treatment B)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
DRUGZibotentan/Dapagliflozin - Formulation 2 (Treatment C)
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
For inclusion in the study participants should fulfil the following criteria: 1. Participants with suitable veins for cannulation or repeated venipuncture. 2. 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 3. Male participant must adhere to the contraception methods. 4. 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. 5. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
Countries
United States
Outcome results
None listed