Safety, Tolerability
Conditions
Brief summary
This is a First in Human (FIH), double-blind, randomised, placebo-controlled study designed to evaluate safety, tolerability and pharmacokinetics (PK) of single and multiple ascending oral doses of AM1476 in healthy subjects.
Detailed description
Part A (SAD); In the SAD part of the study, single oral doses of AM1476 will be administered in up to 9 sequential groups, each consisting of 8 subjects randomised to receive either AM1476 or placebo in a 3:1 ratio. The first 2 subjects in each group will be dosed in a sentinel fashion, 1 subject will receive AM1476 and the other will receive placebo as randomised. Part B (MAD); The MAD part of the study will explore multiple ascending dosing of AM1476 for 10 days. AM1476 will be administered in up to 6 sequential groups, each consisting of 8 subjects randomised to receive either AM1476 or placebo in a 3:1 ratio.
Interventions
DRUGAM1476
AM1476 Capsules
DRUGPlacebo
Placebo Capsules
Sponsors
Covance
AnaMar AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Part A (SAD) Within each group, subjects will be randomised in a 3:1 ratio to receive either AM1476 (n=6) or placebo (n=2). The first 2 subjects in each group will be dosed in a sentinel fashion; 1 subject will receive AM1476 and the other will receive placebo as randomised. Part B (MAD) Within each group, subjects will be randomised in a 3:1 ratio to receive either AM1476 (n=6) or placebo (n=2).
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Males or females, of any race, between 18 and 60 years of age, inclusive. 2. A body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive. 3. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital non-haemolytic hyperbilirubinemia \[eg, suspicion of Gilbert's syndrome based on total and direct bilirubin\] is not acceptable) at Screening and/or Check-in (Day -1) as assessed by the Investigator (or designee). 4. Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception as detailed in Appendix 4. 5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.
Exclusion criteria
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee). 2. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee). 3. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed). 4. Any of the following observed in at least 2 of 3 ECG measurements performed: 1. QTcF \> 450 msec. 2. QRS duration \> 110 msec. 3. PR interval \> 220 msec. 4. findings which would make QTc measurements difficult or QTc data uninterpretable. 5. Any history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, family history of long QT syndrome). 6. Any history or current controlled or uncontrolled hypertension or systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg confirmed by repeat measurement. 7. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in (Day -1). 8. Alcohol consumption of \> 21 units per week for males and \> 14 units per week for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 9. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at Screening or Check-in (Day -1). 10. Positive hepatitis panel and/or positive human immunodeficiency virus test (Appendix 2). 11. Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing. 12. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort, within 30 days prior to dosing, unless deemed acceptable by the Investigator (or designee). 13. Use or intend to use any prescription medications/products other than hormone replacement therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives within 14 days prior to dosing, unless deemed acceptable by the Investigator (or designee). 14. Use or intend to use slow release medications/products considered to still be active within 14 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee). 15. Use or intend to use any non-prescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee). 16. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in (Day -1) or positive cotinine at Screening or Check-in (Day -1). 17. Ingestion of poppy seeds, Seville orange, or grapefruit-containing foods or beverages within 7 days prior to Check-in (Day -1). 18. Subjects who are vegetarians, vegans, or are unable to consume the high-fat breakfast (subjects who will participate in a food-effect evaluation only). 19. Receipt of blood products within 2 months prior to Check-in (Day -1). 20. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. 21. Poor peripheral venous access. 22. Have previously completed or withdrawn from this study or any other study investigating AM1476, and have previously received AM1476. 23. Subjects who are not willing to minimise or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) following administration of study drug until 2 weeks after the last dose. 24. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | Through study completion, an average of 7 weeks | A treatment-emergent adverse-event (TEAE) was defined as an adverse event that started during or after first dosing, or started prior to first dosing and increased in severity after first dosing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | From pre-dose to up to 48 hours post-dose | time to Cmax |
| T½ | From pre-dose to up to 48 hours post-dose | terminal half-life |
| AUC0-tlast | From pre-dose to up to 48 hours post-dose | area under the curve from time 0 to time of the last quantifiable concentration |
| Cmax | From pre-dose to up to 48 hours post-dose | maximum plasma concentration |
| CL/F | From pre-dose to up to 48 hours post-dose | apparent total clearance |
| Vz/F | From pre-dose to up to 48 hours post-dose | apparent volume of distribution during the terminal phase |
| AUC0-tau | Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose. | area under the curve over a dosing interval (tau) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A, Groups 1 to 9: Placebo Part A, Groups 1 to 9: AM1476 placebo-matching capsule, orally once on Days 1 in fasted state
Placebo: Placebo Capsules | 18 |
| Part A, Group 1: AM1476 1 mg Part A, Group 1: AM1476 1 mg capsule, orally once on Day 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 2: AM1476 5 mg Part A, Group 2: AM1476 5 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 3: AM1476 25 mg Part A, Group 3: AM1476 25 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 4: AM1476 125 mg Part A, Group 4: AM1476 125 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 5: AM1476 375 mg Part A, Group 5: AM1476 375 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 7 |
| Part A, Group 6: AM1476 650 mg Part A, Group 6: AM1476 650 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 7: AM1476 950 mg Part A, Group 7: AM1476 950 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 8: AM1476 1500 mg Part A, Group 8: AM1476 1500 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part A, Group 9: AM1476 2400 mg Part A, Group 9: AM1476 2400 mg capsule, orally once on Days 1 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part B, Groups 1 to 3: Placebo Part B, Groups 1 to 3: AM1476 placebo-matching capsule, orally once or twice on Days 1-10 in fasted state
Placebo: Placebo Capsules | 6 |
| Part B, Group 1: AM1476 100 mg QD Part B, Group 1: AM1476 100 mg capsule, orally once on Days 1-10 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part B, Group 2: AM1476 375 mg BID Part B, Group 2: AM1476 375 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state
AM1476: AM1476 Capsules | 6 |
| Part B, Group 3: AM1476 500 mg BID Part B, Group 3: AM1476 500 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state
AM1476: AM1476 Capsules | 6 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A, Groups 1 to 9: Placebo | Part A, Group 1: AM1476 1 mg | Part A, Group 2: AM1476 5 mg | Part A, Group 3: AM1476 25 mg | Part A, Group 4: AM1476 125 mg | Part A, Group 5: AM1476 375 mg | Part A, Group 6: AM1476 650 mg | Part A, Group 7: AM1476 950 mg | Part A, Group 8: AM1476 1500 mg | Part A, Group 9: AM1476 2400 mg | Part B, Groups 1 to 3: Placebo | Part B, Group 1: AM1476 100 mg QD | Part B, Group 2: AM1476 375 mg BID | Part B, Group 3: AM1476 500 mg BID | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.4 years STANDARD_DEVIATION 12.95 | 42.3 years STANDARD_DEVIATION 14.56 | 38.8 years STANDARD_DEVIATION 16.63 | 37.0 years STANDARD_DEVIATION 14.82 | 38.2 years STANDARD_DEVIATION 11.65 | 28.4 years STANDARD_DEVIATION 6.21 | 50.8 years STANDARD_DEVIATION 11.02 | 37.0 years STANDARD_DEVIATION 13.11 | 35.2 years STANDARD_DEVIATION 13.99 | 38.5 years STANDARD_DEVIATION 15.87 | 37.3 years STANDARD_DEVIATION 15.17 | 30.7 years STANDARD_DEVIATION 8.19 | 34.3 years STANDARD_DEVIATION 14.24 | 28.2 years STANDARD_DEVIATION 4.17 | 37.5 years STANDARD_DEVIATION 13.14 |
| Body Mass Index | 25.23 kg/m2 STANDARD_DEVIATION 3.626 | 26.33 kg/m2 STANDARD_DEVIATION 3.912 | 26.03 kg/m2 STANDARD_DEVIATION 4.479 | 25.98 kg/m2 STANDARD_DEVIATION 3.378 | 25.78 kg/m2 STANDARD_DEVIATION 2.662 | 24.67 kg/m2 STANDARD_DEVIATION 3.119 | 26.45 kg/m2 STANDARD_DEVIATION 2.402 | 26.37 kg/m2 STANDARD_DEVIATION 2.382 | 27.18 kg/m2 STANDARD_DEVIATION 5.115 | 24.55 kg/m2 STANDARD_DEVIATION 3.462 | 26.18 kg/m2 STANDARD_DEVIATION 4.659 | 24.83 kg/m2 STANDARD_DEVIATION 3.435 | 23.15 kg/m2 STANDARD_DEVIATION 2.673 | 24.60 kg/m2 STANDARD_DEVIATION 3.2 | 25.48 kg/m2 STANDARD_DEVIATION 3.451 |
| Body Weight | 76.91 kg STANDARD_DEVIATION 13.376 | 85.70 kg STANDARD_DEVIATION 19.447 | 75.58 kg STANDARD_DEVIATION 10.193 | 81.35 kg STANDARD_DEVIATION 11.542 | 78.12 kg STANDARD_DEVIATION 14.972 | 74.60 kg STANDARD_DEVIATION 14.594 | 79.93 kg STANDARD_DEVIATION 10.994 | 76.13 kg STANDARD_DEVIATION 13.65 | 82.35 kg STANDARD_DEVIATION 15.599 | 80.93 kg STANDARD_DEVIATION 14.02 | 81.63 kg STANDARD_DEVIATION 19.397 | 73.05 kg STANDARD_DEVIATION 14.729 | 70.98 kg STANDARD_DEVIATION 15.157 | 78.65 kg STANDARD_DEVIATION 13.827 | 78.07 kg STANDARD_DEVIATION 13.925 |
| Height | 174.3 cm STANDARD_DEVIATION 6.73 | 179.2 cm STANDARD_DEVIATION 10.38 | 171.0 cm STANDARD_DEVIATION 9.61 | 176.9 cm STANDARD_DEVIATION 4.48 | 173.3 cm STANDARD_DEVIATION 10.25 | 173.3 cm STANDARD_DEVIATION 9.6 | 173.7 cm STANDARD_DEVIATION 8.41 | 169.3 cm STANDARD_DEVIATION 8.87 | 174.2 cm STANDARD_DEVIATION 5.98 | 181.3 cm STANDARD_DEVIATION 8.64 | 175.8 cm STANDARD_DEVIATION 9.41 | 170.8 cm STANDARD_DEVIATION 8.16 | 174.3 cm STANDARD_DEVIATION 9.89 | 178.3 cm STANDARD_DEVIATION 5.35 | 174.6 cm STANDARD_DEVIATION 8.25 |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment United Kingdom | 18 participants | 6 participants | 6 participants | 6 participants | 6 participants | 7 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 6 participants | 97 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 4 Participants | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 34 Participants |
| Sex: Female, Male Male | 14 Participants | 5 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 2 Participants | 4 Participants | 5 Participants | 4 Participants | 3 Participants | 4 Participants | 6 Participants | 63 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 3 / 18 | 0 / 6 | 0 / 6 | 4 / 6 | 1 / 6 | 2 / 7 | 3 / 6 | 2 / 6 | 4 / 6 | 5 / 6 | 6 / 6 | 3 / 6 | 2 / 6 | 4 / 6 |
| serious Total, serious adverse events | 0 / 18 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events
A treatment-emergent adverse-event (TEAE) was defined as an adverse event that started during or after first dosing, or started prior to first dosing and increased in severity after first dosing.
Time frame: Through study completion, an average of 7 weeks
Population: The safety analysis set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A, Groups 1 to 9: Placebo | Number of Participants With Treatment-Emergent Adverse Events | 3 Participants |
| Part A, Group 1: AM1476 1 mg | Number of Participants With Treatment-Emergent Adverse Events | 0 Participants |
| Part A, Group 2: AM1476 5 mg | Number of Participants With Treatment-Emergent Adverse Events | 0 Participants |
| Part A, Group 3: AM1476 25 mg | Number of Participants With Treatment-Emergent Adverse Events | 4 Participants |
| Part A, Group 4: AM1476 125 mg | Number of Participants With Treatment-Emergent Adverse Events | 1 Participants |
| Part A, Group 5: AM1476 375 mg | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
| Part A, Group 6: AM1476 650 mg | Number of Participants With Treatment-Emergent Adverse Events | 3 Participants |
| Part A, Group 7: AM1476 950 mg | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
| Part A, Group 8: AM1476 1500 mg | Number of Participants With Treatment-Emergent Adverse Events | 4 Participants |
| Part A, Group 9: AM1476 2400 mg | Number of Participants With Treatment-Emergent Adverse Events | 5 Participants |
| Part B, Groups 1 to 3: Placebo | Number of Participants With Treatment-Emergent Adverse Events | 6 Participants |
| Part B, Group 1: AM1476 100 mg QD | Number of Participants With Treatment-Emergent Adverse Events | 3 Participants |
| Part B, Group 2: AM1476 375 mg BID | Number of Participants With Treatment-Emergent Adverse Events | 2 Participants |
| Part B, Group 3: AM1476 500 mg BID | Number of Participants With Treatment-Emergent Adverse Events | 4 Participants |
Secondary
AUC0-tau
area under the curve over a dosing interval (tau)
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | AUC0-tau | Day 1 | 77.7 h*ng/mL | Geometric Coefficient of Variation 36.8 |
| Part A, Groups 1 to 9: Placebo | AUC0-tau | Day 10 | 110 h*ng/mL | Geometric Coefficient of Variation 16.5 |
| Part A, Group 1: AM1476 1 mg | AUC0-tau | Day 1 | 324 h*ng/mL | Geometric Coefficient of Variation 43.6 |
| Part A, Group 1: AM1476 1 mg | AUC0-tau | Day 10 | 574 h*ng/mL | Geometric Coefficient of Variation 30.6 |
| Part A, Group 2: AM1476 5 mg | AUC0-tau | Day 1 | 702 h*ng/mL | Geometric Coefficient of Variation 22.7 |
| Part A, Group 2: AM1476 5 mg | AUC0-tau | Day 10 | 953 h*ng/mL | Geometric Coefficient of Variation 28.6 |
Secondary
AUC0-tlast
area under the curve from time 0 to time of the last quantifiable concentration
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the AUC was not reported for 4 participants due to less than 3 consecutive quantifiable concentrations (calculation criteria in the Statistical analytical plan).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | AUC0-tlast | NA h*ng/mL | — |
| Part A, Group 1: AM1476 1 mg | AUC0-tlast | 2.77 h*ng/mL | Geometric Coefficient of Variation 26.1 |
| Part A, Group 2: AM1476 5 mg | AUC0-tlast | 15.0 h*ng/mL | Geometric Coefficient of Variation 26.1 |
| Part A, Group 3: AM1476 25 mg | AUC0-tlast | 113 h*ng/mL | Geometric Coefficient of Variation 33.6 |
| Part A, Group 4: AM1476 125 mg | AUC0-tlast | 312 h*ng/mL | Geometric Coefficient of Variation 44.8 |
| Part A, Group 5: AM1476 375 mg | AUC0-tlast | 882 h*ng/mL | Geometric Coefficient of Variation 73.2 |
| Part A, Group 6: AM1476 650 mg | AUC0-tlast | 1280 h*ng/mL | Geometric Coefficient of Variation 46.8 |
| Part A, Group 7: AM1476 950 mg | AUC0-tlast | 3000 h*ng/mL | Geometric Coefficient of Variation 75.2 |
| Part A, Group 8: AM1476 1500 mg | AUC0-tlast | 4900 h*ng/mL | Geometric Coefficient of Variation 28.2 |
Secondary
CL/F
apparent total clearance
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | CL/F | Day 1 | 1220 L/h | Geometric Coefficient of Variation 35 |
| Part A, Groups 1 to 9: Placebo | CL/F | Day 10 | 906 L/h | Geometric Coefficient of Variation 16.5 |
| Part A, Group 1: AM1476 1 mg | CL/F | Day 1 | 1080 L/h | Geometric Coefficient of Variation 45.6 |
| Part A, Group 1: AM1476 1 mg | CL/F | Day 10 | 653 L/h | Geometric Coefficient of Variation 30.6 |
| Part A, Group 2: AM1476 5 mg | CL/F | Day 1 | 673 L/h | Geometric Coefficient of Variation 21.6 |
| Part A, Group 2: AM1476 5 mg | CL/F | Day 10 | 525 L/h | Geometric Coefficient of Variation 28.6 |
Secondary
CL/F
apparent total clearance
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the apparent total clearance was not calculable due to the limited quantifiable AM1476 concentrations available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Group 1: AM1476 1 mg | CL/F | 1480 L/h | Geometric Coefficient of Variation 23.7 |
| Part A, Group 2: AM1476 5 mg | CL/F | 1550 L/h | Geometric Coefficient of Variation 27.4 |
| Part A, Group 3: AM1476 25 mg | CL/F | 1080 L/h | Geometric Coefficient of Variation 31.9 |
| Part A, Group 4: AM1476 125 mg | CL/F | 1030 L/h | Geometric Coefficient of Variation 30.2 |
| Part A, Group 5: AM1476 375 mg | CL/F | 724 L/h | Geometric Coefficient of Variation 71.8 |
| Part A, Group 6: AM1476 650 mg | CL/F | 620 L/h | Geometric Coefficient of Variation 16.9 |
| Part A, Group 7: AM1476 950 mg | CL/F | 495 L/h | Geometric Coefficient of Variation 75 |
| Part A, Group 8: AM1476 1500 mg | CL/F | 487 L/h | Geometric Coefficient of Variation 28 |
Secondary
Cmax
maximum plasma concentration
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | Cmax | Day 1 | 18.8 ng/mL | Geometric Coefficient of Variation 63.5 |
| Part A, Groups 1 to 9: Placebo | Cmax | Day 10 | 26.0 ng/mL | Geometric Coefficient of Variation 40.9 |
| Part A, Group 1: AM1476 1 mg | Cmax | Day 1 | 116 ng/mL | Geometric Coefficient of Variation 52.1 |
| Part A, Group 1: AM1476 1 mg | Cmax | Day 10 | 202 ng/mL | Geometric Coefficient of Variation 48.4 |
| Part A, Group 2: AM1476 5 mg | Cmax | Day 1 | 252 ng/mL | Geometric Coefficient of Variation 41.6 |
| Part A, Group 2: AM1476 5 mg | Cmax | Day 10 | 278 ng/mL | Geometric Coefficient of Variation 32.6 |
Secondary
Cmax
maximum plasma concentration
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the AM1476 concentrations for one participant were below the level of quantification at all timepoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | Cmax | 0.165 ng/mL | Geometric Coefficient of Variation 46.8 |
| Part A, Group 1: AM1476 1 mg | Cmax | 0.785 ng/mL | Geometric Coefficient of Variation 43.4 |
| Part A, Group 2: AM1476 5 mg | Cmax | 3.83 ng/mL | Geometric Coefficient of Variation 36.2 |
| Part A, Group 3: AM1476 25 mg | Cmax | 30.0 ng/mL | Geometric Coefficient of Variation 57.6 |
| Part A, Group 4: AM1476 125 mg | Cmax | 119 ng/mL | Geometric Coefficient of Variation 48.9 |
| Part A, Group 5: AM1476 375 mg | Cmax | 260 ng/mL | Geometric Coefficient of Variation 102.2 |
| Part A, Group 6: AM1476 650 mg | Cmax | 334 ng/mL | Geometric Coefficient of Variation 64.4 |
| Part A, Group 7: AM1476 950 mg | Cmax | 654 ng/mL | Geometric Coefficient of Variation 89.7 |
| Part A, Group 8: AM1476 1500 mg | Cmax | 1250 ng/mL | Geometric Coefficient of Variation 35.8 |
Secondary
T½
terminal half-life
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the t½ was not calculable due to the limited quantifiable AM1476 concentrations available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Group 1: AM1476 1 mg | T½ | 2.52 hour | Geometric Coefficient of Variation 14.8 |
| Part A, Group 2: AM1476 5 mg | T½ | 4.58 hour | Geometric Coefficient of Variation 49.4 |
| Part A, Group 3: AM1476 25 mg | T½ | 8.34 hour | Geometric Coefficient of Variation 40.6 |
| Part A, Group 4: AM1476 125 mg | T½ | 13.7 hour | Geometric Coefficient of Variation 112.8 |
| Part A, Group 5: AM1476 375 mg | T½ | 10.1 hour | Geometric Coefficient of Variation 19.5 |
| Part A, Group 6: AM1476 650 mg | T½ | 7.84 hour | Geometric Coefficient of Variation 9.1 |
| Part A, Group 7: AM1476 950 mg | T½ | 8.91 hour | Geometric Coefficient of Variation 8.7 |
| Part A, Group 8: AM1476 1500 mg | T½ | 7.36 hour | Geometric Coefficient of Variation 24.1 |
Secondary
T½
terminal half-life
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476.~A reliable characterization of the terminal half-life could not be obtained according the calculation criteria in the Statistical analytical plan for 2 participants dosed with 100 mg QD and 1 participant dosed with 375 mg BID on Day 10.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | T½ | Day 1 | 5.70 hour | Geometric Coefficient of Variation 19.6 |
| Part A, Groups 1 to 9: Placebo | T½ | Day 10 | 11.4 hour | Geometric Coefficient of Variation 27.9 |
| Part A, Group 1: AM1476 1 mg | T½ | Day 1 | 3.23 hour | Geometric Coefficient of Variation 8.4 |
| Part A, Group 1: AM1476 1 mg | T½ | Day 10 | 12.8 hour | Geometric Coefficient of Variation 16.6 |
| Part A, Group 2: AM1476 5 mg | T½ | Day 1 | 2.89 hour | Geometric Coefficient of Variation 12.2 |
| Part A, Group 2: AM1476 5 mg | T½ | Day 10 | 15.8 hour | Geometric Coefficient of Variation 21.6 |
Secondary
Tmax
time to Cmax
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | Tmax | Day 1 | 0.500 hour |
| Part A, Groups 1 to 9: Placebo | Tmax | Day 10 | 0.775 hour |
| Part A, Group 1: AM1476 1 mg | Tmax | Day 1 | 1.00 hour |
| Part A, Group 1: AM1476 1 mg | Tmax | Day 10 | 1.00 hour |
| Part A, Group 2: AM1476 5 mg | Tmax | Day 1 | 1.00 hour |
| Part A, Group 2: AM1476 5 mg | Tmax | Day 10 | 1.25 hour |
Secondary
Tmax
time to Cmax
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the AM1476 concentrations for one participant were below the level of quantification at all timepoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A, Groups 1 to 9: Placebo | Tmax | 1.50 hour |
| Part A, Group 1: AM1476 1 mg | Tmax | 1.75 hour |
| Part A, Group 2: AM1476 5 mg | Tmax | 1.00 hour |
| Part A, Group 3: AM1476 25 mg | Tmax | 0.983 hour |
| Part A, Group 4: AM1476 125 mg | Tmax | 1.00 hour |
| Part A, Group 5: AM1476 375 mg | Tmax | 1.01 hour |
| Part A, Group 6: AM1476 650 mg | Tmax | 1.51 hour |
| Part A, Group 7: AM1476 950 mg | Tmax | 1.00 hour |
| Part A, Group 8: AM1476 1500 mg | Tmax | 1.00 hour |
Secondary
Vz/F
apparent volume of distribution during the terminal phase
Time frame: From pre-dose to up to 48 hours post-dose
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476. At the 1 mg AM1476 dose level, the apparent volume of distribution during the terminal phase was not calculable due to the limited quantifiable AM1476 concentrations available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A, Group 1: AM1476 1 mg | Vz/F | 5380 L | Geometric Coefficient of Variation 35.6 |
| Part A, Group 2: AM1476 5 mg | Vz/F | 10200 L | Geometric Coefficient of Variation 30.8 |
| Part A, Group 3: AM1476 25 mg | Vz/F | 13000 L | Geometric Coefficient of Variation 60.7 |
| Part A, Group 4: AM1476 125 mg | Vz/F | 20400 L | Geometric Coefficient of Variation 163 |
| Part A, Group 5: AM1476 375 mg | Vz/F | 10500 L | Geometric Coefficient of Variation 92.7 |
| Part A, Group 6: AM1476 650 mg | Vz/F | 7010 L | Geometric Coefficient of Variation 13 |
| Part A, Group 7: AM1476 950 mg | Vz/F | 6360 L | Geometric Coefficient of Variation 75.5 |
| Part A, Group 8: AM1476 1500 mg | Vz/F | 5180 L | Geometric Coefficient of Variation 43.2 |
Secondary
Vz/F
apparent volume of distribution during the terminal phase
Time frame: Day 1: From pre-dose up to 24 hours post first dose after QD dosing and from pre-dose up to 12 hours post first dose after BID dosing. Day 10: From pre-dose up to 48 hours post last dose.
Population: The pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of AM1476.~A reliable characterization of the apparent volume of distribution during the terminal phase could not be obtained according the calculation criteria in the Statistical analytical plan for 2 participants dosed with 100 mg QD and 1 participant dosed with 375 mg BID on Day 10.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A, Groups 1 to 9: Placebo | Vz/F | Day 1 | 10100 L | Geometric Coefficient of Variation 40.4 |
| Part A, Groups 1 to 9: Placebo | Vz/F | Day 10 | 14200 L | Geometric Coefficient of Variation 29.4 |
| Part A, Group 1: AM1476 1 mg | Vz/F | Day 1 | 5020 L | Geometric Coefficient of Variation 38.3 |
| Part A, Group 1: AM1476 1 mg | Vz/F | Day 10 | 12800 L | Geometric Coefficient of Variation 37 |
| Part A, Group 2: AM1476 5 mg | Vz/F | Day 1 | 2800 L | Geometric Coefficient of Variation 27.5 |
| Part A, Group 2: AM1476 5 mg | Vz/F | Day 10 | 12000 L | Geometric Coefficient of Variation 48.9 |