Safety, Pharmacokinetics, Pharmacodynamics, Food Effect
Conditions
Keywords
AZD7986, Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Food Effect, First-in-human, Single Ascending Dose, Multiple Ascending Dose, Healthy Subjects
Brief summary
This is a phase I, randomised, single-blind placebo-controlled, 2-part study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and food effect of single and multiple oral doses of AZD7986 in healthy volunteers
Interventions
DRUGAZD7986, oral solution, 1 to 50 mg/mL
Starting dose in single ascending dose part: 5 mg
DRUGPlacebo, oral solution
Matching placebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provision of signed and dated written informed consent prior to any study specific procedures. 2. Healthy male or female subjects aged 18 to 50 years (inclusive) at screening with suitable veins for cannulation or repeated venepuncture. 3. Females must be of non-child-bearing potential, confirmed at screening by fulfilling one of the following criteria: * Post-menopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in the post menopausal range. * Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 4. Male subjects must be non fertile, i.e., surgically sterilised with documentation of azoospermia or must practice an effective contraceptive method to prevent pregnancies. Effective contraceptive methods are: * Sexual abstinence from before the first administration of the IMP until 3 months after final administration of the IMP, only if this is in line with the preferred and usual lifestyle of the subject. * Use of a condom plus spermicide agent in addition to having their partner use another acceptable method (oral or injectable hormonal contraceptives, contraceptive patch, intrauterine devices, vaginal hormonal rings, vaginal diaphragm or cervical caps) from before the first administration of the IMP until 3 months after final administration of the IMP. * Subject's sexual partner is of non childbearing potential, i.e., post menopausal or surgically sterilised (e.g., tubal ligation, hysterectomy in medical history). 5. Have a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive at screening.
Exclusion criteria
* History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study. * History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. * Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP. * Subject has increased risk of infection: * History and/or presence of tuberculosis (TB); positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), subjects who have resided in regions where tuberculosis and mycosis are endemic during 90 days before screening, or who intend to visit such a region during the duration of the study i.e. deserts areas, Eastern Europe, Central and South America, Africa except Egypt, Russia, Asia, Indonesia * Oral body temperature of \> 37.7°C on Day -1, or as judged by the Investigator. * Blood neutrophil count \< 1.7 x109/L (Screening and Day -1 morning sample). * Is in high risk-group for HIV infection within the last 6 months (i.e., men who have had unprotected sex with men, women who have had sex without a condom with men who have sex with men, people who have had sex without a condom with a person who has lived or travelled in Africa, people who inject drugs, people who have had sex without a condom with somebody who has injected drugs, people who have caught another sexually transmitted infection, people who have received a blood transfusion while in Africa, eastern Europe, the countries of the former Soviet Union, Asia or central and southern America). * Other latent or chronic infections (e.g., recurrent sinusitis, genital or ocular herpes, urinary tract infection) or at risk of infection (surgery, trauma, or significant infection) within 90 days of screening, or history of skin abscesses within 90 days of screening. * Clinically significant lower respiratory tract infection not resolved within 4 weeks prior to screening, as determined by the Investigator. * Volunteers with active malignancy or neoplastic disease in the previous 5 years other than superficial basal cell carcinoma. * Disease history suggesting abnormal immune function. * Volunteers who have received live or live-attenuated vaccine in the 4 weeks prior to dosing. * High-sensitivity C-reactive protein above upper limit of laboratory reference range at screening and on Day -1. * Some subjects lacking functional dipeptidyl peptidase 1 (DPP1) enzyme have been described to have periodontitis and palmoplantar hyperkeratosis: * For Part 1a and Part 1b: Subjects with signs of current gingivitis/periodontitis. Gingival evaluation (by inspection) will be performed by a dental hygienist or trained study physician. * For Part 2: Subjects with a history of recurring gingivitis/periodontitis or signs of current gingivitis/periodontitis. Gingival evaluation will be performed by a dental hygienist or trained study physician. Evaluation of bleeding propensity due to gingivitis will be performed by using dental hygienist instrumentation. Exact measurement of gum pockets is not needed. * Subjects with a history of hyperkeratosis or erythema in palms or soles.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2 |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the accumulation ratio for Cmax (Rac(Cmax)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as Cmax Day 21/Cmax Day 1 |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess renal clearance from 0 to 48 hours (CLR0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state) |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess cumulative amount of analyte excreted from 0 to 24 hours (CumAe0-24) for Part 2 |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the temporal change parameter (TCP) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC Day 1, if extrapolated part was less than 20% |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state) |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state) |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess percentage of dose excreted unchanged into the urine from 0 to 24 hours (Cumfe0 24) for Part 2 |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess renal clearance from 0 to 24 hours (CLR0-24) for Part 2 |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess Cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48)) for Part 2 |
| Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2 |
| Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Part 1a and 1b: Day -1, Day 1 to Day 3 (spontaneous, at pre-dose, 3, 12, 24, 48 and 72 hours [h] post-dose), Day 4, Day 5 and follow-up (7-10 days after dosing [not for participants included in Part 1b]); Part 2: Day -1, Day 1 to Day 21/28 and follow-up | To investigate the safety and tolerability of AZD7986 by assessment of AEs (non-serious and serious) following administration of oral solution in SAD (Part 1a - fasted state and 1b - fed state) and MAD (Part 2) |
| Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2 |
| Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration. |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Note: Day 1 data calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data |
| Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCτ) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. AUCτ: AUC from time zero to 24 hours post-dose presented on Day1 |
| Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assessthe observed maximum plasma concentration (Cmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Cmax was taken directly from the individual concentration-time curve |
| Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the time to reach maximum observed concentration (tmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve |
| Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the apparent terminal elimination half-life (t½.λz) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve. Note: Day 1 data were calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data |
| Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD |
| Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the mean residence time (MRT) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2 |
| Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the apparent clearance (CL/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; CL/F for parent drug was estimated as dose divided by AUC |
| Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the the apparent volume of distribution (Vz/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz |
| Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28 | To assess the accumulation ratio for (Rac(AUC(0-τ)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC(0-24) Day 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Food on Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration. |
| Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve |
| Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve |
| Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD |
| Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD |
| Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC |
| Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz |
| Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | At Day 16, 21 ((last dosing day in Cohort 1), 25, 28 (last sampling day in Cohort 1 and last dosing day in Cohorts 2 and 3), 32, 38, 41 and 52 | Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker |
| Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | At Day 12 (pre-dose, 6 hours and 12 hours) | Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker |
| Effect of Food on Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h) | To assess the effect of food by evaluating the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD |
Countries
United Kingdom
Participant flow
Recruitment details
This study was conducted at PAREXEL Early Phase Clinical Unit London, Level 7, Northwick Park Hospital in London. Healthy male and female participants were enrolled.
Pre-assignment details
In Part 1 and Part 2, participants underwent a screening visit within 28 days before receiving the first dose of investigational medicinal product (IMP). Participants were admitted to the study centre 1 day before administration of the IMP (Day -1).
Participants by arm
| Arm | Count |
|---|---|
| AZD7986 5 mg (Fasted State) - SAD Participants received single dose of oral solution of AZD7986 5mg on Day 1 in fasted state. | 6 |
| AZD7986 15 mg (Fasted State) - SAD Participants received single dose of oral solution of AZD7986 15mg on Day 1in fasted state. | 6 |
| AZD7986 35 mg (Fasted State) - SAD Participants received single dose of oral solution of AZD7986 35mg on Day 1 in fasted state. | 6 |
| AZD7986 50 mg (Fasted State) - SAD Participants received single dose of oral solution of AZD7986 50mg on Day 1 in fasted state. | 6 |
| AZD7986 65 mg (Fasted State) - SAD Participants received single dose of oral solution of AZD7986 65mg on Day 1 in fasted state. | 6 |
| AZD7986 35 mg (Fed State) - SAD Participants of Cohorts 3 from Part 1a received single dose of oral solution of AZD7986 35 mg on Day 1 in fed state after a washout of at least 7 days. | 5 |
| AZD7986 10 mg - MAD Participants received single dose (morning) of oral solution of AZD7986 10 mg for 28 days (fasted or fed state, depending on Part 1b results). Participants were fasted until 1 hour after dosing when a light breakfast was provided. | 6 |
| AZD7986 25 mg - MAD Participants received single dose (morning) of oral solution of AZD7986 25 mg for 28 days (fasted or fed state, depending on Part 1b results). Participants were fasted until 1 hour after dosing when a light breakfast was provided. | 8 |
| AZD7986 40 mg - MAD Participants received single dose (morning) of oral solution of AZD7986 40 mg for 28 days (fasted or fed state, depending on Part 1b results). Participants were fasted until 1 hour after dosing when a light breakfast was provided. | 10 |
| Placebo - Part 1a (Fasted) Randomized participants received orally AZD7986 matching placebo oral solution on Day 1 in fasted state. | 15 |
| Placebo - Part 1b (Fed State) Randomized participants received orally AZD7986 matching placebo oral solution on Day 1 in fed state. | 3 |
| Placebo - Part 2 Randomized participants received orally AZD7986 matching placebo oral solution for 28 days (fasted/fed state, based on part 1b results). | 12 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1a (Fasted State)- SAD | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part 2 - Multiple Ascending Dose (MAD) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | AZD7986 15 mg (Fasted State) - SAD | AZD7986 65 mg (Fasted State) - SAD | AZD7986 35 mg (Fasted State) - SAD | AZD7986 5 mg (Fasted State) - SAD | Total | AZD7986 50 mg (Fasted State) - SAD | Placebo - Part 1a (Fasted) | AZD7986 35 mg (Fed State) - SAD | Placebo - Part 1b (Fed State) | AZD7986 40 mg - MAD | AZD7986 10 mg - MAD | AZD7986 25 mg - MAD | Placebo - Part 2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Part 1a | 29.7 Years STANDARD_DEVIATION 8.78 | 29.7 Years STANDARD_DEVIATION 6.65 | 26.2 Years STANDARD_DEVIATION 3.66 | 28.5 Years STANDARD_DEVIATION 5.39 | 29.2 Years STANDARD_DEVIATION 7.14 | 32.2 Years STANDARD_DEVIATION 10.5 | — | — | — | — | — | — | — |
| Age, Continuous Part 1a Placebo | — | — | — | — | 29.9 Years STANDARD_DEVIATION 7.24 | — | 29.9 Years STANDARD_DEVIATION 7.24 | — | — | — | — | — | — |
| Age, Continuous Part 1b | — | — | — | — | 26.6 Years STANDARD_DEVIATION 3.91 | — | — | 26.6 Years STANDARD_DEVIATION 3.91 | — | — | — | — | — |
| Age, Continuous Part 1b Placebo | — | — | — | — | 28.7 Years STANDARD_DEVIATION 8.5 | — | — | — | 28.7 Years STANDARD_DEVIATION 8.5 | — | — | — | — |
| Age, Continuous Part 2 | — | — | — | — | 34.8 Years STANDARD_DEVIATION 8.05 | — | — | — | — | 34.4 Years STANDARD_DEVIATION 9.17 | 30.7 Years STANDARD_DEVIATION 5.65 | 38.4 Years STANDARD_DEVIATION 7.25 | — |
| Age, Continuous Part 2 Placebo | — | — | — | — | 36.2 Years STANDARD_DEVIATION 7.2 | — | — | — | — | — | — | — | 36.2 Years STANDARD_DEVIATION 7.2 |
| Sex: Female, Male Part 1a Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 1a Male | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 45 Participants | 6 Participants | 15 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 1b Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 1b Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 0 Participants | 0 Participants | 5 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 2 Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Part 2 Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 36 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 10 Participants | 6 Participants | 8 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 5 | 0 / 24 | 0 / 15 | 0 / 3 | 0 / 12 |
| other Total, other adverse events | 8 / 30 | 2 / 5 | 23 / 24 | 8 / 15 | 1 / 3 | 8 / 12 |
| serious Total, serious adverse events | 0 / 30 | 0 / 5 | 0 / 24 | 0 / 15 | 0 / 3 | 0 / 12 |
Outcome results
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD
To assess the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 14.23 Litre/Hour | Standard Deviation 7.577 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 8.606 Litre/Hour | Standard Deviation 0.9321 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 6.395 Litre/Hour | Standard Deviation 1.281 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 6.938 Litre/Hour | Standard Deviation 1.777 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 6.371 Litre/Hour | Standard Deviation 1.317 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 7.363 Litre/Hour | Standard Deviation 1.81 |
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD
To assess the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 19.96 Hour | Standard Deviation 3.416 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 25.92 Hour | Standard Deviation 4.452 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 23.80 Hour | Standard Deviation 3.328 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 24.52 Hour | Standard Deviation 5.836 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 25.50 Hour | Standard Deviation 7.254 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 24.24 Hour | Standard Deviation 4.259 |
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD
To assess the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 385.1 Litre | Standard Deviation 129.6 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 318.8 Litre | Standard Deviation 46.72 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 215.8 Litre | Standard Deviation 29.62 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 236.8 Litre | Standard Deviation 39.64 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 231.0 Litre | Standard Deviation 67.56 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 249.5 Litre | Standard Deviation 24.96 |
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD
To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration.
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 915.3 h·nmol/L | Geometric Coefficient of Variation 46.1 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 4165 h·nmol/L | Geometric Coefficient of Variation 10.8 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 13230 h·nmol/L | Geometric Coefficient of Variation 19.6 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 17590 h·nmol/L | Geometric Coefficient of Variation 25.2 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 24710 h·nmol/L | Geometric Coefficient of Variation 21.5 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 11550 h·nmol/L | Geometric Coefficient of Variation 22.6 |
95% CI: [1.183, 1.391]
90% CI: [83.72, 98.31]
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD
To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 839.0 h·nmol/L | Geometric Coefficient of Variation 48.3 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 3855 h·nmol/L | Geometric Coefficient of Variation 9.3 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 12430 h·nmol/L | Geometric Coefficient of Variation 18.3 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 16470 h·nmol/L | Geometric Coefficient of Variation 22.7 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 22880 h·nmol/L | Geometric Coefficient of Variation 21.2 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 10790 h·nmol/L | Geometric Coefficient of Variation 20.2 |
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD
To assess the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 27.03 Hour | Standard Deviation 4.373 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 34.94 Hour | Standard Deviation 5.863 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 32.15 Hour | Standard Deviation 5.003 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 32.19 Hour | Standard Deviation 8.36 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 33.76 Hour | Standard Deviation 10.35 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 33.73 Hour | Standard Deviation 6.429 |
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD
To assess the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 50.74 nmol/L | Geometric Coefficient of Variation 47.2 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 202.3 nmol/L | Geometric Coefficient of Variation 16 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 668.1 nmol/L | Geometric Coefficient of Variation 26.7 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 1035 nmol/L | Geometric Coefficient of Variation 11.5 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 1358 nmol/L | Geometric Coefficient of Variation 24.2 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 434.8 nmol/L | Geometric Coefficient of Variation 14 |
Comparison: Dose proportionality was analyzed by power model. Slope parameter was obtained via linear least squares.95% CI: [1.198, 1.406]
90% CI: [55.07, 74.7]
Primary
Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD
To assess the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.50 Hour | Full Range 47.2 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.75 Hour | Full Range 16 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.75 Hour | Full Range 26.7 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.64 Hour | Full Range 11.5 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.75 Hour | Full Range 24.2 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 4.00 Hour | Full Range 14 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD
To assess area under the plasma concentration-time curve from time zero to the end of the dosing interval (AUCτ) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. AUCτ: AUC from time zero to 24 hours post-dose presented on Day1
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 1277 h·nmol/L | Geometric Coefficient of Variation 18.9 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 3259 h·nmol/L | Geometric Coefficient of Variation 15.9 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 6433 h·nmol/L | Geometric Coefficient of Variation 31 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 2834 h·nmol/L | Geometric Coefficient of Variation 35.1 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 7499 h·nmol/L | Geometric Coefficient of Variation 27.4 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCτ) for Part 2 - MAD | 15660 h·nmol/L | Geometric Coefficient of Variation 43.3 |
95% CI: [0.9513, 1.504]
90% CI: [140.61, 180.7]
90% CI: [138.23, 166.74]
90% CI: [146.67, 171.67]
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD
To assess the mean residence time (MRT) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 18.56 Hour | Standard Deviation 2.245 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 21.84 Hour | Standard Deviation 3.067 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 22.64 Hour | Standard Deviation 5.844 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 33.73 Hour | Standard Deviation 9.663 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 40.16 Hour | Standard Deviation 10.58 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Mean Residence Time (MRT) for Part 2 - MAD | 37.46 Hour | Standard Deviation 8.157 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD
To assess the accumulation ratio for Cmax (Rac(Cmax)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as Cmax Day 21/Cmax Day 1
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | NA Ratio | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | NA Ratio | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | NA Ratio | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | 1.799 Ratio | Standard Deviation 0.3084 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | 1.667 Ratio | Standard Deviation 0.2007 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for Cmax (Rac(Cmax)) for Part 2 - MAD | 1.881 Ratio | Standard Deviation 0.4015 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD
To assess the accumulation ratio for (Rac(AUC(0-τ)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC(0-24) Day 1
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | NA Ratio | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | NA Ratio | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | NA Ratio | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | 2.257 Ratio | Standard Deviation 0.456 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | 2.330 Ratio | Standard Deviation 0.4828 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Accumulation Ratio for (Rac(AUC(0-τ)) for Part 2 - MAD | 2.476 Ratio | Standard Deviation 0.4521 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD
To assess the apparent clearance (CL/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; CL/F for parent drug was estimated as dose divided by AUC
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 13.61 Litre/Hour | Standard Deviation 2.665 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 12.20 Litre/Hour | Standard Deviation 2.485 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 10.24 Litre/Hour | Standard Deviation 4.206 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 8.786 Litre/Hour | Standard Deviation 2.772 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 8.165 Litre/Hour | Standard Deviation 2.025 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 2 - MAD | 6.577 Litre/Hour | Standard Deviation 2.867 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD
To assess the apparent terminal elimination half-life (t½.λz) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve. Note: Day 1 data were calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 12.82 Hour | Standard Deviation 1.477 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 14.85 Hour | Standard Deviation 2.244 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 15.85 Hour | Standard Deviation 4.132 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 25.85 Hour | Standard Deviation 5.501 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 33.78 Hour | Standard Deviation 10.31 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 2 - MAD | 30.04 Hour | Standard Deviation 5.483 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD
To assess the the apparent volume of distribution (Vz/F) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 248.9 Litre | Standard Deviation 38.94 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 256.7 Litre | Standard Deviation 36.11 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 222.7 Litre | Standard Deviation 65.93 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 311.8 Litre | Standard Deviation 56.96 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 393.2 Litre | Standard Deviation 163.1 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 2 - MAD | 269.6 Litre | Standard Deviation 79.13 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD
To assess the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Note: Day 1 data calculated over a 24 hour period and was therefore not comparable with the Day 21 and Day 28 data
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 1778 h·nmol/L | Geometric Coefficient of Variation 21.3 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 4957 h·nmol/L | Geometric Coefficient of Variation 19.5 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 9866 h·nmol/L | Geometric Coefficient of Variation 35.8 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 5565 h·nmol/L | Geometric Coefficient of Variation 54.3 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 16660 h·nmol/L | Geometric Coefficient of Variation 44.2 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 2 - MAD | 33220 h·nmol/L | Geometric Coefficient of Variation 58.5 |
90% CI: [140.61, 180.7]
90% CI: [138.23, 166.74]
90% CI: [146.67, 171.67]
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD
To assess the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 1278 h·nmol/L | Geometric Coefficient of Variation 18.9 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 3256 h·nmol/L | Geometric Coefficient of Variation 15.9 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 6427 h·nmol/L | Geometric Coefficient of Variation 31 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 5135 h·nmol/L | Geometric Coefficient of Variation 49.4 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 14320 h·nmol/L | Geometric Coefficient of Variation 39.5 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Analyte Concentration (AUC(0-last)) for Part 2 - MAD | 29550 h·nmol/L | Geometric Coefficient of Variation 53.5 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD
To assessthe observed maximum plasma concentration (Cmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2. Cmax was taken directly from the individual concentration-time curve
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 138.6 nmol/L | Geometric Coefficient of Variation 18.3 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 350.9 nmol/L | Geometric Coefficient of Variation 19.3 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 672.0 nmol/L | Geometric Coefficient of Variation 37 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 246.3 nmol/L | Geometric Coefficient of Variation 26.2 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 598.1 nmol/L | Geometric Coefficient of Variation 15.5 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 2 - MAD | 1235 nmol/L | Geometric Coefficient of Variation 37.7 |
95% CI: [0.9285, 1.385]
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD
To assess the temporal change parameter (TCP) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; estimated as AUC(0-τ) Day 21/AUC Day 1, if extrapolated part was less than 20%
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | NA Ratio | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | NA Ratio | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | NA Ratio | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | 1.610 Ratio | Standard Deviation 0.2539 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | 1.535 Ratio | Standard Deviation 0.2479 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Temporal Change Parameter (TCP) for Part 2 - MAD | 1.599 Ratio | Standard Deviation 0.2082 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD
To assess the time to reach maximum observed concentration (tmax) following a single AZD7986 dose on Day 1 and daily dosing on Days 21 or 28 at 10, 25 and 40 mg in Part 2; tmax was taken directly from the individual concentration-time curve
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 1.51 Hour | Full Range 21.3 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 0.75 Hour | Full Range 19.5 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 0.75 Hour | Full Range 35.8 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 1.50 Hour | — |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 0.75 Hour | — |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 2 - MAD | 1.12 Hour | — |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD
To assess cumulative amount of analyte excreted from 0 to 24 hours (CumAe0-24) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 2295 nmol | Standard Deviation 638.1 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 5540 nmol | Standard Deviation 1305 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 11390 nmol | Standard Deviation 2415 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 4002 nmol | Standard Deviation 1402 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 11960 nmol | Standard Deviation 4665 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 24 Hours (CumAe0-24)) Parameters for Part 2 - MAD | 24970 nmol | Standard Deviation 8075 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD
To assess Cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48)) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | NA nmol | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | NA nmol | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | NA nmol | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | 6525 nmol | Standard Deviation 2684 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | 18680 nmol | Standard Deviation 8765 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Parameter for Part 2 - MAD | 36160 nmol | Standard Deviation 12030 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD
To assess cumulative amount of analyte excreted from 0 to 48 hours (CumAe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1318 nmol | Standard Deviation 348.5 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 4820 nmol | Standard Deviation 1096 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 16530 nmol | Standard Deviation 2145 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 19660 nmol | Standard Deviation 4521 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 27770 nmol | Standard Deviation 10200 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Cumulative Amount of Analyte Excreted From 0 to 48 Hours (CumAe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 18420 nmol | Standard Deviation 2554 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD
To assess percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 11.09 Percentage of dose excreted unchanged | Standard Deviation 2.931 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 13.51 Percentage of dose excreted unchanged | Standard Deviation 3.074 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 19.86 Percentage of dose excreted unchanged | Standard Deviation 2.578 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 16.53 Percentage of dose excreted unchanged | Standard Deviation 3.802 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 17.97 Percentage of dose excreted unchanged | Standard Deviation 6.598 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 22.13 Percentage of dose excreted unchanged | Standard Deviation 3.069 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD
To assess renal clearance from 0 to 48 hours (CLR0-48) after single dose administration of AZD7986 oral solution in Part 1a (fasted state) and 1b (fed state)
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 h); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1.734 Liter/hour | Standard Deviation 0.368 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1.544 Liter/hour | Standard Deviation 0.2898 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1.619 Liter/hour | Standard Deviation 0.2101 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1.430 Liter/hour | Standard Deviation 0.1561 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 1.477 Liter/hour | Standard Deviation 0.5187 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK Parameter (Renal Clearance From 0 to 48 Hours (CLR0-48)) Following Administration of Single Dose Oral Solution for Part 1a and 1b - SAD | 2.097 Liter/hour | Standard Deviation 0.1921 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD
To assess percentage of dose excreted unchanged into the urine from 0 to 24 hours (Cumfe0 24) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 9.650 Percentage of dose excreted unchanged | Standard Deviation 2.683 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 9.319 Percentage of dose excreted unchanged | Standard Deviation 2.195 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 11.98 Percentage of dose excreted unchanged | Standard Deviation 2.539 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 16.83 Percentage of dose excreted unchanged | Standard Deviation 5.894 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 20.12 Percentage of dose excreted unchanged | Standard Deviation 7.847 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 24 Hours (Cumfe0-24)) Parameter for Part 2 - MAD | 26.25 Percentage of dose excreted unchanged | Standard Deviation 8.489 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD
To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | NA Percentage of dose excreted unchanged | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | NA Percentage of dose excreted unchanged | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | NA Percentage of dose excreted unchanged | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | 27.44 Percentage of dose excreted unchanged | Standard Deviation 11.29 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | 31.42 Percentage of dose excreted unchanged | Standard Deviation 14.74 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Percentage of Dose Excreted Unchanged Into the Urine From 0 to 48 Hours (Cumfe0 48)) Parameter for Part 2 - MAD | 38.01 Percentage of dose excreted unchanged | Standard Deviation 12.65 |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD
To assess renal clearance from 0 to 24 hours (CLR0-24) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | 1.784 Liter/hour | Standard Deviation 0.4606 |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | 1.685 Liter/hour | Standard Deviation 0.3441 |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | 1.782 Liter/hour | Standard Deviation 0.3841 |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | NA Liter/hour | — |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | NA Liter/hour | — |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 24 Hours (CLR0-24)) Parameter for Part 2 - MAD | NA Liter/hour | — |
Primary
Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD
To assess Percentage of dose excreted unchanged into the urine from 0 to 48 hours (Cumfe0 48) for Part 2
Time frame: Day 1 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24 h); Day 21 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 9, 12, 24, 72, 96 h) and Day 28
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | NA Liter/hour | — |
| Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | NA Liter/hour | — |
| Part 2 - Multiple Ascending Dose (MAD) | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | NA Liter/hour | — |
| Placebo - Part 1a (Fasted State)- SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | 1.508 Liter/hour | Standard Deviation 0.438 |
| Placebo - Part 1b (Fed State) - SAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | 1.618 Liter/hour | Standard Deviation 0.5085 |
| Placebo - Part 2 - MAD | Rate and Extent of Absorption of AZD7986 by Assessment of Urine PK (Renal Clearance From 0 to 48 Hours (CLR0-48)) Parameter for Part 2 - MAD | 1.527 Liter/hour | Standard Deviation 0.3418 |
Primary
Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2)
To investigate the safety and tolerability of AZD7986 by assessment of AEs (non-serious and serious) following administration of oral solution in SAD (Part 1a - fasted state and 1b - fed state) and MAD (Part 2)
Time frame: Part 1a and 1b: Day -1, Day 1 to Day 3 (spontaneous, at pre-dose, 3, 12, 24, 48 and 72 hours [h] post-dose), Day 4, Day 5 and follow-up (7-10 days after dosing [not for participants included in Part 1b]); Part 2: Day -1, Day 1 to Day 21/28 and follow-up
Population: All randomized subjects who received at least one dose of IMP were included in the safety analysis for the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 8 Participants |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 0 Participants |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
| Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
| Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 2 Participants |
| Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 0 Participants |
| Part 2 - Multiple Ascending Dose (MAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 23 Participants |
| Part 2 - Multiple Ascending Dose (MAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Part 2 - Multiple Ascending Dose (MAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 1 Participants |
| Part 2 - Multiple Ascending Dose (MAD) | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
| Placebo - Part 1a (Fasted State)- SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 8 Participants |
| Placebo - Part 1a (Fasted State)- SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
| Placebo - Part 1a (Fasted State)- SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Placebo - Part 1a (Fasted State)- SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 0 Participants |
| Placebo - Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Placebo - Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 0 Participants |
| Placebo - Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 1 Participants |
| Placebo - Part 1b (Fed State) - SAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
| Placebo - Part 2 - MAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE | 8 Participants |
| Placebo - Part 2 - MAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE leading to discontinuation of AZD7986 | 0 Participants |
| Placebo - Part 2 - MAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any serious adverse event (SAE) (including death) | 0 Participants |
| Placebo - Part 2 - MAD | Safety and Tolerability of AZD7986 by Assessment of the Number of Adverse Events (AEs) Following Administration of Oral Solution in Single Ascending Dose (SAD - Part 1a and 1b) and Multiple Ascending Doses (MAD -Part 2) | Any AE with outcome = death | 0 Participants |
Secondary
Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2
Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker
Time frame: At Day 12 (pre-dose, 6 hours and 12 hours)
Population: All participants who receiving at least 1 dose of AZD7986 or placebo and who had at least 1 pre-dose and 1 post-dose measurement for either NE (NE1 or NE2), and who had no major protocol deviations thought to impact on the analysis of the PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, Pre-dose | 2.757 10^9 neutrophils/L | Standard Deviation 0.4178 |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 12 h | NA 10^9 neutrophils/L | — |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 6 h | NA 10^9 neutrophils/L | — |
| Part 1b (Fed State) - SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, Pre-dose | 2.881 10^9 neutrophils/L | Standard Deviation 0.5222 |
| Part 1b (Fed State) - SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 12 h | 3.454 10^9 neutrophils/L | Standard Deviation 0.7448 |
| Part 1b (Fed State) - SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 6 h | 3.401 10^9 neutrophils/L | Standard Deviation 1.049 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 6 h | 3.129 10^9 neutrophils/L | Standard Deviation 0.721 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, Pre-dose | 2.560 10^9 neutrophils/L | Standard Deviation 0.9108 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 12 h | 3.460 10^9 neutrophils/L | Standard Deviation 0.5248 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, Pre-dose | 2.945 10^9 neutrophils/L | Standard Deviation 0.7966 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 12 h | 3.247 10^9 neutrophils/L | Standard Deviation 0.7622 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Absolute Neutrophil Count (ANC) in All Cohorts of Part 2 | Day 12, 6 h | 3.402 10^9 neutrophils/L | Standard Deviation 1.178 |
Secondary
Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2
Absolute neutrophil count (ANC) was evaluated as part of the safety laboratory assessments and to evaluate the pharmacodynamics (PD) marker
Time frame: At Day 16, 21 ((last dosing day in Cohort 1), 25, 28 (last sampling day in Cohort 1 and last dosing day in Cohorts 2 and 3), 32, 38, 41 and 52
Population: All participants who receiving at least 1 dose of AZD7986 or placebo and who had at least 1 pre-dose and 1 post-dose measurement for either NE (NE1 or NE2), and who had no major protocol deviations thought to impact on the analysis of the PD data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 38 | NA Percentage change in NE activity | — |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 41 | NA Percentage change in NE activity | — |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 21 | -26.13 Percentage change in NE activity | Standard Deviation 3.116 |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 16 | -7.53 Percentage change in NE activity | Standard Deviation 11.59 |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 28 | -39.22 Percentage change in NE activity | Standard Deviation 9.141 |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 52 | NA Percentage change in NE activity | — |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 25 | -30.15 Percentage change in NE activity | Standard Deviation 8.412 |
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 32 | NA Percentage change in NE activity | — |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 28 | -45.05 Percentage change in NE activity | Standard Deviation 8.304 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 16 | -28.25 Percentage change in NE activity | Standard Deviation 22.33 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 21 | -36.73 Percentage change in NE activity | Standard Deviation 11.76 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 38 | -54.42 Percentage change in NE activity | Standard Deviation 6.8 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 32 | -53.35 Percentage change in NE activity | Standard Deviation 8.292 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 41 | -53.46 Percentage change in NE activity | Standard Deviation 9.774 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 25 | -40.06 Percentage change in NE activity | Standard Deviation 6.609 |
| Part 1b (Fed State) - SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 52 | -17.73 Percentage change in NE activity | Standard Deviation 18.07 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 21 | -52.31 Percentage change in NE activity | Standard Deviation 14.9 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 25 | -59.02 Percentage change in NE activity | Standard Deviation 11.77 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 38 | -65.44 Percentage change in NE activity | Standard Deviation 7.556 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 28 | -55.24 Percentage change in NE activity | Standard Deviation 9.087 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 41 | -62.56 Percentage change in NE activity | Standard Deviation 8.324 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 32 | -46.29 Percentage change in NE activity | Standard Deviation 37.55 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 52 | -21.31 Percentage change in NE activity | Standard Deviation 18.07 |
| Part 2 - Multiple Ascending Dose (MAD) | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 16 | -28.10 Percentage change in NE activity | Standard Deviation 16.87 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 52 | -20.98 Percentage change in NE activity | Standard Deviation 15.32 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 32 | -6.216 Percentage change in NE activity | Standard Deviation 14.28 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 38 | -19.51 Percentage change in NE activity | Standard Deviation 10.74 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 41 | -18.14 Percentage change in NE activity | Standard Deviation 15.62 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 28 | -16.36 Percentage change in NE activity | Standard Deviation 22.03 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 16 | 7.39 Percentage change in NE activity | Standard Deviation 13.06 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 21 | 1.39 Percentage change in NE activity | Standard Deviation 20.14 |
| Placebo - Part 1a (Fasted State)- SAD | Assessment of Mean Normalized Relative Neutrophil Elastase (NE) Activity in All Cohorts of Part 2 | Day 25 | -5.15 Percentage change in NE activity | Standard Deviation 14.14 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the apparent clearance (CL/F) for Part 1a (fasted state) and 1b (fed state) - SAD; CL/F for parent drug was estimated as dose divided by AUC
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 6.395 Litre/Hour | Standard Deviation 1.281 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Clearance (CL/F) for Part 1a and 1b - SAD | 7.363 Litre/Hour | Standard Deviation 1.81 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the half life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½.λz) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 23.80 Hour | Standard Deviation 3.328 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Terminal Elimination Half-life (t½.λz) for Part 1a and 1b - SAD | 24.24 Hour | Standard Deviation 4.259 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the apparent volume of distribution (Vz/F) for Part 1a (fasted state) and 1b (fed state) - SAD; Vz/F at terminal phase (extravascular administration) was estimated by dividing the apparent clearance (CL/F) by λz
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 215.8 Litre | Standard Deviation 29.62 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Apparent Volume of Distribution (Vz/F) for Part 1a and 1b - SAD | 249.5 Litre | Standard Deviation 24.96 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the area under plasma concentration-time curve from zero extrapolated to infinity (AUC) for Part 1a (fasted state) and 1b (fed state) - SAD. AUC was estimated by AUC(0 last) + Clast/λz where Clast was the last observed quantifiable concentration.
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 13230 h·nmol/L | Geometric Coefficient of Variation 19.6 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Area Under Plasma Concentration-time Curve From Zero Extrapolated to Infinity (AUC) for Part 1a and 1b - SAD | 11550 h·nmol/L | Geometric Coefficient of Variation 22.6 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the area under the plasma concentration versus time curve, from time zero to the time of the last quantifiable analyte concentration (AUC(0-last)) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 12430 h·nmol/L | Geometric Coefficient of Variation 18.3 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Area Under the Plasma Concentration Versus Time Curve, From Time Zero to the Time of the Last Quantifiable Concentration (AUC(0-last)) for Part 1a and 1b - SAD | 10790 h·nmol/L | Geometric Coefficient of Variation 20.2 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the mean residence time (MRT) for Part 1a (fasted state) and 1b (fed state) - SAD
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 32.15 Hour | Standard Deviation 5.003 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Mean Residence Time (MRT) for Part 1a and 1b - SAD | 33.73 Hour | Standard Deviation 6.429 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the observed maximum plasma concentration (Cmax) for Part 1a (fasted state) and 1b (fed state) - SAD. Cmax was taken directly from the individual concentration-time curve
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 668.1 nmol/L | Geometric Coefficient of Variation 26.7 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Observed Maximum Plasma Concentration (Cmax) for Part 1a and 1b - SAD | 434.8 nmol/L | Geometric Coefficient of Variation 14 |
Secondary
Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD
To assess the effect of food by evaluating the time to reach maximum observed concentration (tmax) for Part 1a (fasted state) and 1b (fed state) - SAD; tmax was taken directly from the individual concentration-time curve
Time frame: At Day 1 (Pre-dose, 0.5, 1, 2, 3, 4, 5, 7, 8, 9, 12 hours); Day 2 (24 h); Day 3 (48 h); Day 4 (72 h) and Day 5 (96 h)
Population: The pharmacokinetic analysis (PK) analysis set consisted of all subjects in the safety analysis set who received at least 1 dose of AZD7986 and had evaluable PK data.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Part 1a (Fasted State) - Single Ascending Dose (SAD) | Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 0.75 Hour | Full Range 26.7 |
| Part 1b (Fed State) - SAD | Effect of Food on Absorption AZD7986 by Assessment of the Time to Reach Maximum Observed Concentration (Tmax) for Part 1a and 1b - SAD | 4.00 Hour | Full Range 14 |