Number of patients with Adverse Events (AEs) due to AZD5817
To assess the adverse events as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. Adverse Events will be collected from the start of randomization throughout the treatment period up to and including the follow-up visit. Serious adverse events (SAEs) will be recorded from the time of informed consent.
Supine vital sign (Systolic Blood pressure [BP])
To assess the vital sign as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.
Supine vital sign (pulse rate)
To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Number of participants with abnormal findings in electrocardiograms (ECGs) (safety ECGs, digital ECGs [dECG])
To assess any clinically important abnormalities in the cardiovascular system functioning as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. A 12-lead 10-second safety ECG will be performed with the Schiller Cardiovit CS-200 recorder immediately following all scheduled dECGs. 12-lead continuous dECG will be recorded over at least 5 minutes with the Schiller Cardiovit CS-200 recorder and transmitted to the AstraZeneca central dECG repository, according to AstraZeneca ECG Center´s standard procedures for settings, recording, and transmission of dECGs. For dECG, QTcF (QT interval corrected for heart rate using Fridericia's formula) will be calculated as QTcF =(QT*(RR/1000)^(-1/3)), where RR (the time between corresponding points on 2 consecutive R waves on ECG) is presented in milliseconds. Heart rate (HR) will also be calculated, based on the RR interval.
Number of participants with abnormal cardiac telemetry
To assess any clinically important abnormalities in the cardiovascular system functioning (heart beat/rythm) using 2-lead real-time telemetry ECG as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The telemetry monitoring system will be reviewed by the Investigator or research nurse and paper printouts of any clinically important events will be stored as source data.
Number of participants with abnormal findings in physical examinations
To assess any clinically important abnormal findings in physical conditions as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses. The complete physical examinations include an assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. The brief physical examinations include an assessment of the general appearance, skin, cardiovascular system, respiratory and abdomen. Any new or aggravated clinically relevant abnormal medical finding at a physical examination as compared with the baseline assessment will be reported as an adverse event.
Laboratory assessment: Hematology (leukocyte count)
To assess the leukocyte count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Supine vital sign (diastolic BP)
To assess the vital sign as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (sodium)
To assess the clinical chemistry value (sodium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Urinalysis (glucose)
To assess urinalysis (glucose) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Red blood cell [RBC] count)
To assess the RBC count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Hemoglobin [Hb])
To assess the Hb as a criterion of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Hematocrit [HCT])
To assess the HCT as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Mean corpuscular volume [MCV])
To assess the MCV as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Mean corpuscular hemoglobin [MCH])
To assess the MCH as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Mean corpuscular hemoglobin concentration [MCHC])
To assess the MCHC as a variable of safety and tolerability variable of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (potassium)
To assess the clinical chemistry value (potassium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (urea)
To assess the clinical chemistry value (urea) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (creatinine)
To assess the clinical chemistry value (creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (albumin)
To assess the clinical chemistry value (albumin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (calcium)
To assess the clinical chemistry value (calcium) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (phosphate)
To assess the clinical chemistry value (phosphate) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (glucose (fasting))
To assess the clinical chemistry value (glucose (fasting)) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (insulin)
To assess the clinical chemistry value (insulin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (fibrinogen)
To assess the clinical chemistry value (fibrinogen) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (thyroid-stimulating hormone)
To assess the clinical chemistry value (thyroid-stimulating hormone) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Urinalysis (blood)
To assess urinalysis (blood) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for blood, a microscopy test will be performed to assess RBC, white blood cell [WBC], casts [cellular, granular, hyaline]).
Laboratory assessment: Urinalysis (protein)
To assess urinalysis (protein) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses. If urinalysis is positive for protein, a microscopy test will be performed to assess RBC, WBC, casts [cellular, granular, hyaline]).
Laboratory assessment: Urinalysis (urine creatinine)
To assess urinalysis (urine creatinine) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Differential Count)
To assess the differential count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Platelets)
To assess the platelets as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Hematology (Reticulocytes absolute count)
To assess the reticulocytes absolute count as a variable of safety and tolerability of AZD5718 following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (High sensitivity-C-reactive protein [CRP])
To assess the clinical chemistry value (CRP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Free T4)
To assess the clinical chemistry value (Free T4) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Alkaline phosphatase [ALP])
To assess the clinical chemistry value (ALP) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Alanine aminotransferase [ALT])
To assess the clinical chemistry value (ALT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Aspartate aminotransferase [AST])
To assess the clinical chemistry value (AST) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Gamma glutamyl transpeptidase [GGT])
To assess the clinical chemistry value (GGT) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Total Bilirubin)
To assess the clinical chemistry value (total bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Unconjugated bilirubin)
To assess the clinical chemistry value (unconjugated bilirubin) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Glutamate dehydrogenase)
To assess the clinical chemistry value (glutamate dehydrogenase) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Laboratory assessment: Clinical chemistry (Lactate dehydrogenase [LDH])
To assess the clinical chemistry value (LDH) as a variable of safety and tolerability of AZD5718, following oral administration of single and multiple ascending doses.
Plasma PK assessment: Observed maximum plasma concentration (Cmax) assessment for AZD5817 after single and repeated oral dosing
To assess Cmax of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Time to reach peak or maximum observed concentration following drug administration (tmax) assessment for AZD5817 after single and repeated oral dosing
To assess tmax of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Terminal rate constant (λZ) assessment for AZD5817 after single and repeated oral dosing
To assess λZ of AZD5718 after single and repeated oral dosing. λZ will be estimated by log-linear least-squares regression of the terminal part of the concentration-time curve.
Plasma PK assessment: Terminal half-life (t½λz) assessment for AZD5817 after single and repeated oral dosing
To assess t½λz of AZD5718 after single and repeated oral dosing. t½λz will be estimated as (ln2)/λZ.
Plasma PK assessment: Area under the plasma concentration-time curve from time zero to 24 hours after dosing (AUC(0-24)) assessment for AZD5817 after single and repeated oral dosing
To assess AUC(0-24) of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC(0-last)) assessment for AZD5817 after single and repeated oral dosing
To assess AUC(0-last) of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Area under the plasma concentration-curve over the dosing interval (AUC(0-τ)) assessment for AZD5817 after single and repeated oral dosing
To assess AUC(0-τ) of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Area under the concentration-time curve from time zero extrapolated to infinity (AUC) assessment for AZD5817 after single and repeated oral dosing
To assess AUC of AZD5718 after single and repeated oral dosing. AUC is estimated by AUC(0-last) + Clast/λZ where Clast is the last observed quantifiable concentration.
Plasma PK assessment: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) assessment for AZD5817 after single and repeated oral dosing
To assess CL/F of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Mean Residence Time (MRT) assessment for AZD5817 after single and repeated oral dosing
To assess MRT of AZD5718 after single and repeated oral dosing.
Plasma PK assessment: Apparent volume of distribution for parent drug at terminal phase (extravascular administration), (Vz/F) assessment for AZD5817 after single and repeated oral dosing
To assess Vz/F of AZD5718 after single and repeated oral dosing. Vz/F will be estimated by dividing the apparent clearance (CL/F) by λZ.
Plasma PK assessment: Observed minimum concentration, (Cmin) assessment for AZD5817 after single and repeated oral dosing (Day 10)
To assess Cmin of AZD5718 after single and repeated oral dosing. Cmin will be taken directly from the individual concentration-time curve.
Plasma PK assessment: Observed average concentration (Cavg) assessment for AZD5817 after single and repeated oral dosing (Day 10)
To assess Cavg of AZD5718 after single and repeated oral dosing. Cavg will be taken directly from the individual concentration-time curve.
Plasma PK assessment: Accumulation ratio (Rac Cmax) assessment for AZD5817 after single and repeated oral dosing
To assess Rac Cmax of AZD5718 after single and repeated oral dosing. Rac Cmax will be calculated as Cmax Day 10/ Cmax Day 1.
Plasma PK assessment: Accumulation ratio (Rac AUC) assessment for AZD5817 after single and repeated oral dosing
To assess Rac AUC of AZD5718 after single and repeated oral dosing. Rac AUC will be calculated as AUCτ Day 10/ AUCτ Day 1.
Plasma PK assessment: Temporal change parameter in systemic exposure (TCP) assessment for AZD5817 after single and repeated oral dosing
To assess TCP of AZD5718 after single and repeated oral dosing. TCP will be calculated as AUCτDay 10/AUCDay 1.
Urine PK assessment: Cumulative amount of unchanged drug excreted in urine from time zero to the last sampling interval (Ae(0-last)) assessment for AZD5817 after single and repeated oral dosing
To assess Ae(0-last) of AZD5718 after single and repeated oral dosing.
Urine PK assessment: Fraction of dose excreted unchanged into the urine from time zero to the last sampling interval measured time point for an analyte (Fe(0-last)) assessment for AZD5817 after single and repeated oral dosing
To assess Fe(0-last) of AZD5718 after single and repeated oral dosing. Fe(0-last) will be estimated by dividing Ae(0-last) by dose.
Urine PK assessment: Renal clearance of drug from plasma (CLR) assessment for AZD5817 after single and repeated oral dosing
To assess CLR of AZD5718 after single and repeated oral dosing. CLR will be estimated by dividing Ae(0-last) by AUC(0-t)).
PD parameter: urine Leukotriene E4 (LTE4) assessment for AZD5817 after single and repeated oral dosing
To evaluate the PD of AZD5718, by assessment of urine LTE4 (u-LTE4), after single and repeated oral dosing.