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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Zibotentan capsule will be administered orally as multiple doses in Part 1 and as single dose in Part 2.
Dapagliflozin tablet will be administered orally as single dose in Part 2.
Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
Research Site
Brooklyn, Maryland, United States
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Day 1 through Day 3 of each treatment period
Part 2: Time to reach peak or maximum observed concentration (tmax)
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Zibotentan/Dapagliflozin tablet will be administered orally as single dose in Part 2.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: From Sceerning to Follow-up Visit approximately 40 days for Part 1 and 49 days for Part 2