This study is randomized, single-blind, placebo-controlled Phase 1 study aimed to assess the safety and efficacy, pharmacokinetics and pharmacodynamics of multiple doses of oral AZD4831 in healthy Japanese and Chinese volunteers
This is a Phase I, randomized, single-blind, placebo-controlled, multiple-ascending dose (MAD), sequential-group study in healthy Japanese (Part 1, Cohorts 1, 2, and 3) and Chinese (Part 2, Cohort 4) male subjects, conducted at a single study center. Four cohorts are planned, but one additional cohort may be enrolled based on a Safety Review Committee (SRC) decision. The 4 multiple dose levels are planned as follows: * Cohort 1: Dose 1 * Cohort 2: Dose 2 * Cohort 3: Dose 3 * Cohort 4: Dose 2 A randomization ratio of 3:1 (AZD4831 versus placebo) will be used. For each cohort the study will comprise: * Screening Period of a maximum of 28 days. * A Treatment Period during which subjects are resident in the study center from the day before first dosing with the Investigational Medicinal Product (Day -1) until at least 48 hours after last dosing on Day 10; subjects will be discharged on Day 12. * Three Follow-up Visits on Day 14, Day 16 (±1 day), and Day 20 (±1 day). * A Final Follow-up Visit on Day 24 (±2 days). Each subject will be involved in the study for 8 to 9 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
32
Research Site
Glendale, California, United States
Number of subjects with adverse events (AEs)/serious adverse events
To assess AEs as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Time frame: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal blood pressure (BP) and pulse
To assess BP and pulse rate as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Time frame: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal electrocardiogram (ECG)
To assess change ECG as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Time frame: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abnormal abnormal clinical chemistry/hematology/urinalysis
To assess clinical chemistry/hematology/urinalysis as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Time frame: Screening through follow-up visit (upto 9 weeks)
Number of subjects with abormal physical examination results
To assess physical examination as a variable of safety and tolerability of AZD4831 following oral administration of multiple-ascending doses at steady state in healthy Japanese and Chinese subjects.
Time frame: Screening through follow-up visit (upto 9 weeks)
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Plasma Cmax: Maximum observed plasma concentration
To characterize the Cmax of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: Pre-dose (pre); 0.25,0.5,1,1.5,2,3,4,6,8,12 h post-dose (post); Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Cmax/D
To characterize the Cmax/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma tmax: Time to reach peak or maximum observed concentration following drug administration
To characterize the tmax of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Ctrough: Observed trough plasma concentration
To characterize the Ctrough of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma t1/2λz: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve
To characterize the t1/2λz of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plamsa AUCτ : Area under the plasma concentration-time curve within the dosing interval
To characterize the AUCτ of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCτ/D
To characterize the AUCτ/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma CL/F: Apparent total body clearance of drug from plasma after extravascular administration (Day 10)
To characterize the CL/F of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Vz/F:Apparent volume of distribution for parent drug at terminal phase after extravascular administration
To characterize the Vz/F of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf: Area under the concentration-time curve from time zero extrapolated to infinity
To characterize the AUCinf of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma AUCinf/D: Area under the plasma concentration-time curve from time zero extrapolated to infinity divided by dose
To characterize the AUCinf/D of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(AUC): Accumulation ratio based upon AUC
To characterize the Rac(AUC) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Plasma Rac(Cmax): Accumulation ratio based upon Cmax
To characterize the Rac(Cmax) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day 1: pre; 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 2-9: Pre; Day 10: Pre and at 0.25,0.5,1,1.5,2,3,4,6,8,12 h post; Day 11:24 and 36 h post; Day 12: 48 h post; Day 16:96,144, and 240 h post; Day 24:336 h post
Urine Ae(t1-t2): Amount of analyte excreted into the urine from time t1 to t2
To characterize the Ae(t1-t2) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine Ae(0-last): Cumulative amount of analyte excreted at the last sampling interval
To characterize the Ae(0-last) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(t1-t2): Fraction of dose (expressed as a percentage) excreted unchanged into the urine from time t1 to t2
To characterize the %fe(t1-t2) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine %fe(0-last): Percentage of dose excreted unchanged into the urine from time zero to the last measured time point for an analyte
To characterize the %fe(0-last) of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post
Urine CLR: Renal clearance of drug from plasma, estimated by dividing Ae(0-last) by AUC(0-t)
To characterize the CLR of AZD4831 following multiple-ascending doses in healthy Japanese and Chinese subjects.
Time frame: Day1 : Pre; Day 10: 0 to 3, 3 to 6, 6 to 9, 9 to 12, 12 to 24 h post