Healthy
Conditions
Brief summary
This first-in-human study has three parts. In Parts A and B, the safety, tolerability, and pharmacokinetics (PK) will be evaluated following administration of single and multiple doses of KRP-A218, including food-effect. In Part C, the drug-drug interaction (DDI) with itraconazole will be evaluated.
Interventions
DRUGKRP-A218
KRP-A218 tablet
DRUGPlacebo
Placebo tablet
DRUGitraconazole
10 mg/mL oral solution
Sponsors
Kyorin Pharmaceutical Co.,Ltd
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Male or female adults, between 20 and 55 years of age, inclusive. * Body weight ≥50 kg, with body mass index (BMI) between 18.0 and 30.0 kg/m\^2, inclusive. * In good health, at Screening or Day -1 as assessed by the Investigator. * Females will not be pregnant or lactating, and females of childbearing potential will agree to use contraception and to not donate eggs (ova, oocytes). Males will agree to use contraception and to not donate sperm. * Able to comprehend and willing to sign an informed consent form (ICF) and to abide by the study restrictions. Key
Exclusion criteria
* 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. * Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing. * 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. * Use or intend to use any prescription medications/products within 14 days or 5 half-lives (whichever is longer) prior to dosing, unless deemed acceptable by the Investigator. * Use or intend to use slow release medications/products considered to still be active within 14 days prior to dosing, unless deemed acceptable by the Investigator. * Use or intend to use any nonprescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant derived preparations within 7 days prior to dosing, unless deemed acceptable by the Investigator. * Use of tobacco or nicotine-containing products within 3 months prior to Day -1, or positive cotinine test at screening or Day -1. * Ingestion of poppy seed-, Seville orange-, or grapefruit-containing foods or beverages within 7 days prior to Day -1. * Consumption of caffeine- or xanthine-containing foods and beverages within 36 hours prior to Day -1. * Participation in strenuous exercised within 7 days prior to Day -1. * Receipt of blood products within 2 months prior to Day -1. * Donation of blood from 3 months prior to screening, plasma from 2 weeks prior to screening, or platelets from 6 weeks prior to screening. * Poor peripheral venous access. * Have previously completed or withdrawn from this study or have previously received the investigational medicinal product (IMP). * Subject is, in the opinion of the Investigator, unlikely to comply with the protocol or unsuitable to participate in this study for any reason. Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of Participants With Adverse Events | Screening to follow-up (Approximately 6 weeks) | A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded. |
| Part B: Number of Participants With Adverse Events | Screening to follow-up (Approximately 8 weeks) | A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded. |
| Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | Days 1 to 11 | The area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity) following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Days 1 to 11 | The area under concentration-time curve from time 0 extrapolated to last quantifiable concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Maximum Observed Concentration (Cmax) | Days 1 to 11 | The maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Time of the Maximum Observed Concentration (Tmax) | Days 1 to 11 | The time of the maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Apparent Terminal Elimination Half-life (t1/2) | Days 1 to 11 | The apparent terminal elimination half-life following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Apparent Total Clearance (CL/F) | Days 1 to 11 | The apparent total clearance following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
| Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Days 1 to 11 | The apparent volume of distribution during the terminal phase following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Days 1 and 14 | Assessment of the area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast) |
| Part B: Maximum Observed Concentration (Cmax) | Days 1 and 14 | Assessment of the maximum observed concentration (Cmax) |
| Part B: Minimum Observed Concentration (Cmin) | Day 14 | Assessment of the minimum observed concentration (Cmin) |
| Part B: Time of the Maximum Observed Concentration (Tmax) | Days 1 and 14 | Assessment of the time of the maximum observed concentration (Tmax) |
| Part B: Apparent Terminal Elimination Half-life (t1/2) | Days 1 and 14 | Assessment of the apparent terminal elimination half-life (t1/2) |
| Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | Day 1 | Area under concentration-time curve from time 0 extrapolated to infinity following single oral dose of KRP-A218 |
| Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Days 1 and 14 | Assessment of the apparent volume of distribution during the terminal phase (Vz/F) |
| Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T) | Day 14 | Observed accumulation ratio based on area under the concentration-time curve over a dosing interval (ARAUC0-T) in Part B |
| Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax) | Day 14 | Observed accumulation ratio based on maximum observed concentration during the dosing interval (ARCmax) in Part B |
| Part C: Number of Participants With Adverse Events | Screening to follow-up (Approximately 7 weeks) | A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded. |
| Part B: Apparent Total Clearance (CL/F) | Days 1 and 14 | Assessment of the apparent total clearance (CL/F) |
| Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 1 | Area under curve from time 0 to the time of the last quantifiable concentration following single oral dose of KRP-A218 |
| Part A: Maximum Observed Concentration (Cmax) | Day 1 | Maximum observed concentration following single oral dose of KRP-A218 |
| Part A: Time of the Maximum Observed Concentration (Tmax) | Day 1 | Time of the maximum observed concentration following single oral dose of KRP-A218 |
| Part A: Apparent Terminal Elimination Half-life (t1/2) | Day 1 | Apparent terminal elimination half-life following single oral dose of KRP-A218 |
| Part A: Apparent Total Clearance (CL/F) | Day 1 | Apparent total clearance following single oral dose of KRP-A218 |
| Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 1 | Apparent volume of distribution during the terminal phase following single oral dose of KRP-A218 |
| Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Days 1 and 14 | Assessment of the area under the concentration-time curve over a dosing interval (AUC0-τ) |
| Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | Day 1 | Assessment of the area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity) |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo Single ascending dose study.
Participants received a single order dose of placebo with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours.
For those randomized to the Fasted/Fed group, on Day 1, Treatment Period 2, male participants also received a single order dose of placebo 30 minutes after starting a high-fat breakfast. | 12 |
| Part A: 1 mg KRP-A218 (Fasted Male) Single ascending dose study.
Participants received a single order dose of 1 mg KRP-A218 with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours. | 5 |
| Part A: 3 mg KRP-A218 (Fasted/Fed Male) Single ascending dose study.
On Day 1, Treatment Period 1, male participants received a single order dose of 3 mg KRP-A218 after an overnight fast of at least 10 hours.
On Day 1, Treatment Period 2, male participants received a single order dose of 3 mg KRP-A218 30 minutes after starting a high-fat breakfast. | 6 |
| Part A: 3 mg KRP-A218 (Fasted Female) Single ascending dose study.
Female participants received a single order dose of 3 mg KRP-A218 with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours. | 6 |
| Part A: 6 mg KRP-A218 (Fasted Male) Single ascending dose study.
Male participants received a single order dose of 6 mg KRP-A218 with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours. | 6 |
| Part A: 12 mg KRP-A218 (Fasted Male) Single ascending dose study.
Male participants received a single order dose of 12 mg KRP-A218 with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours. | 6 |
| Part A: 21 mg KRP-A218 (Fasted Male) Single ascending dose study.
Male participants received a single order dose of 21 mg KRP-A218 with approximately 240 mL of room temperature water after an overnight fast of at least 10 hours. | 6 |
| Part B: Placebo Multiple ascending dose study.
Participants received once daily oral doses of placebo from Days 1 to 14. Each dose was administered with approximately 240 mL of room temperature water. | 8 |
| Part B: 2 mg KRP-A218 Multiple ascending dose study.
Participants received once daily oral doses of 2 mg KRP-A218 from Days 1 to 14. Each dose was administered with approximately 240 mL of room temperature water. | 8 |
| Part B: 4 mg KRP-A218 Multiple ascending dose study.
Participants received once daily oral doses of 4 mg KRP-A218 from Days 1 to 14. Each dose was administered with approximately 240 mL of room temperature water. | 8 |
| Part B: 8 mg KRP-A218 Multiple ascending dose study.
Participants received once daily oral doses of 8 mg KRP-A218 from Days 1 to 14. Each dose was administered with approximately 240 mL of room temperature water. | 8 |
| Part B: 11 mg KRP-A218 Multiple ascending dose study.
Participants received once daily oral doses of 11 mg KRP-A218 from Days 1 to 14. Each dose was administered with approximately 240 mL of room temperature water. | 8 |
| Part C: Drug-drug Interaction Study Days 1 and 11: single oral dose of 1 mg KRP-A218 (with approximately 240 mL of room temperature water), in the fasted state.
Day 4: 2 × single oral doses of 200 mg itraconazole solution (10 mg/mL) administered with no additional water, approximately 12 hours apart, in the fasted state.
Days 5 to 13: single oral doses of 200 mg itraconazole, solution (10 mg/mL) administered with no additional water, in the fasted state. | 12 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Part A: Placebo | Part A: 1 mg KRP-A218 (Fasted Male) | Part A: 3 mg KRP-A218 (Fasted/Fed Male) | Part A: 3 mg KRP-A218 (Fasted Female) | Part A: 6 mg KRP-A218 (Fasted Male) | Part A: 12 mg KRP-A218 (Fasted Male) | Part A: 21 mg KRP-A218 (Fasted Male) | Part B: Placebo | Part B: 2 mg KRP-A218 | Part B: 4 mg KRP-A218 | Part B: 8 mg KRP-A218 | Part B: 11 mg KRP-A218 | Part C: Drug-drug Interaction Study | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 6.43 | 27.4 years STANDARD_DEVIATION 2.41 | 35.0 years STANDARD_DEVIATION 12.68 | 36.3 years STANDARD_DEVIATION 11.91 | 38.8 years STANDARD_DEVIATION 9.39 | 31.0 years STANDARD_DEVIATION 6.13 | 30.8 years STANDARD_DEVIATION 4.71 | 36.5 years STANDARD_DEVIATION 13.78 | 32.3 years STANDARD_DEVIATION 9.77 | 38.4 years STANDARD_DEVIATION 10.77 | 37.5 years STANDARD_DEVIATION 9.96 | 31.9 years STANDARD_DEVIATION 9.48 | 36.4 years STANDARD_DEVIATION 11.01 | 34.3 years STANDARD_DEVIATION 9.69 |
| Body Mass Index | 24.43 kilograms/metres squared STANDARD_DEVIATION 2.411 | 25.00 kilograms/metres squared STANDARD_DEVIATION 2.769 | 25.12 kilograms/metres squared STANDARD_DEVIATION 3.589 | 23.90 kilograms/metres squared STANDARD_DEVIATION 3.239 | 26.35 kilograms/metres squared STANDARD_DEVIATION 1.866 | 25.55 kilograms/metres squared STANDARD_DEVIATION 1.981 | 25.03 kilograms/metres squared STANDARD_DEVIATION 2.166 | 24.48 kilograms/metres squared STANDARD_DEVIATION 1.855 | 25.06 kilograms/metres squared STANDARD_DEVIATION 2.304 | 25.15 kilograms/metres squared STANDARD_DEVIATION 2.718 | 24.36 kilograms/metres squared STANDARD_DEVIATION 3.225 | 26.39 kilograms/metres squared STANDARD_DEVIATION 3.321 | 24.38 kilograms/metres squared STANDARD_DEVIATION 1.847 | 24.95 kilograms/metres squared STANDARD_DEVIATION 2.519 |
| Body Weight | 74.44 kilograms STANDARD_DEVIATION 10.453 | 82.08 kilograms STANDARD_DEVIATION 12.815 | 72.50 kilograms STANDARD_DEVIATION 9.134 | 65.23 kilograms STANDARD_DEVIATION 8.138 | 85.80 kilograms STANDARD_DEVIATION 8.734 | 83.20 kilograms STANDARD_DEVIATION 7.654 | 82.37 kilograms STANDARD_DEVIATION 11.934 | 74.34 kilograms STANDARD_DEVIATION 7.558 | 82.01 kilograms STANDARD_DEVIATION 10.405 | 83.29 kilograms STANDARD_DEVIATION 8.061 | 74.75 kilograms STANDARD_DEVIATION 14.155 | 81.33 kilograms STANDARD_DEVIATION 11.106 | 79.20 kilograms STANDARD_DEVIATION 7.228 | 78.33 kilograms STANDARD_DEVIATION 10.653 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 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 | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 12 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 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 | 0 Participants |
| Height | 174.42 centimetres STANDARD_DEVIATION 9.549 | 180.80 centimetres STANDARD_DEVIATION 4.97 | 170.00 centimetres STANDARD_DEVIATION 3.347 | 165.33 centimetres STANDARD_DEVIATION 4.082 | 180.33 centimetres STANDARD_DEVIATION 7.394 | 180.33 centimetres STANDARD_DEVIATION 2.503 | 181.00 centimetres STANDARD_DEVIATION 7.239 | 174.13 centimetres STANDARD_DEVIATION 3.796 | 180.63 centimetres STANDARD_DEVIATION 5.449 | 182.13 centimetres STANDARD_DEVIATION 4.121 | 174.63 centimetres STANDARD_DEVIATION 8.634 | 175.63 centimetres STANDARD_DEVIATION 5.975 | 180.25 centimetres STANDARD_DEVIATION 7.275 | 176.96 centimetres STANDARD_DEVIATION 7.593 |
| Race (NIH/OMB) American Indian or Alaska Native | 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 | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 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 | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 5 Participants | 5 Participants | 4 Participants | 6 Participants | 4 Participants | 5 Participants | 6 Participants | 7 Participants | 7 Participants | 7 Participants | 7 Participants | 12 Participants | 85 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 10 Participants | 5 Participants | 6 Participants | 0 Participants | 6 Participants | 6 Participants | 6 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 8 Participants | 12 Participants | 91 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 | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 4 / 12 | 3 / 5 | 4 / 6 | 3 / 6 | 2 / 6 | 2 / 6 | 3 / 6 | 2 / 6 | 6 / 8 | 3 / 8 | 7 / 8 | 5 / 8 | 5 / 8 | 5 / 12 | 3 / 12 | 6 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 5 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Part A: Number of Participants With Adverse Events
A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.
Time frame: Screening to follow-up (Approximately 6 weeks)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Placebo | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: Placebo | Part A: Number of Participants With Adverse Events | Overall TEAEs | 4 participants |
| Part A: Placebo | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: Placebo | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 3 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 4 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 3 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 2 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 2 participants |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 3 participants |
| Part A: 21 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Overall TEAEs | 2 participants |
| Part A: 21 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 21 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Death | 0 participants |
| Part A: 21 mg KRP-A218 (Fasted Male) | Part A: Number of Participants With Adverse Events | TEAEs Leading to Discontinuation | 0 participants |
Primary
Part B: Number of Participants With Adverse Events
A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.
Time frame: Screening to follow-up (Approximately 8 weeks)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Placebo | Part B: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: Placebo | Part B: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: Placebo | Part B: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: Placebo | Part B: Number of Participants With Adverse Events | Overall TEAEs | 6 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Number of Participants With Adverse Events | Overall TEAEs | 3 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Number of Participants With Adverse Events | Overall TEAEs | 7 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Number of Participants With Adverse Events | Overall TEAEs | 5 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 1 participants |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part B: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part B: Number of Participants With Adverse Events | Overall TEAEs | 5 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part B: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part B: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
Primary
Part C: Apparent Terminal Elimination Half-life (t1/2)
The apparent terminal elimination half-life following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Apparent Terminal Elimination Half-life (t1/2) | 15.9 hours | Geometric Coefficient of Variation 10.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Apparent Terminal Elimination Half-life (t1/2) | 26.5 hours | Geometric Coefficient of Variation 15.5 |
Primary
Part C: Apparent Total Clearance (CL/F)
The apparent total clearance following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Apparent Total Clearance (CL/F) | 5.24 Liter Per Hour | Geometric Coefficient of Variation 23.9 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Apparent Total Clearance (CL/F) | 2.78 Liter Per Hour | Geometric Coefficient of Variation 25 |
Primary
Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F)
The apparent volume of distribution during the terminal phase following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 120 liters | Geometric Coefficient of Variation 17.6 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 106 liters | Geometric Coefficient of Variation 23.8 |
Primary
Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)
The area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity) following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic Population)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 191 ng*h/mL | Geometric Coefficient of Variation 23.9 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 360 ng*h/mL | Geometric Coefficient of Variation 25 |
90% CI: [1.74, 2.04]
Primary
Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)
The area under concentration-time curve from time 0 extrapolated to last quantifiable concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 182 ng*h/mL | Geometric Coefficient of Variation 22.8 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 306 ng*h/mL | Geometric Coefficient of Variation 23.5 |
90% CI: [1.57, 1.79]
Primary
Part C: Maximum Observed Concentration (Cmax)
The maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part C: Maximum Observed Concentration (Cmax) | 10.7 ng/mL | Geometric Coefficient of Variation 20.3 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Maximum Observed Concentration (Cmax) | 12.2 ng/mL | Geometric Coefficient of Variation 20.9 |
90% CI: [1.09, 1.21]
Primary
Part C: Time of the Maximum Observed Concentration (Tmax)
The time of the maximum observed concentration following Oral Dose Administration of KRP-A218 Alone and in Combination with Itraconazole
Time frame: Days 1 to 11
Population: Pharmacokinetic population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part C: Time of the Maximum Observed Concentration (Tmax) | 3.00 hours |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Time of the Maximum Observed Concentration (Tmax) | 2.00 hours |
Secondary
Part A: Apparent Terminal Elimination Half-life (t1/2)
Apparent terminal elimination half-life following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Apparent Terminal Elimination Half-life (t1/2) | 18.5 hours | Geometric Coefficient of Variation 12 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 15.0 hours | Geometric Coefficient of Variation 27.4 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 15.7 hours | Geometric Coefficient of Variation 22.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 18.1 hours | Geometric Coefficient of Variation 29.3 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 17.6 hours | Geometric Coefficient of Variation 11.1 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 16.4 hours | Geometric Coefficient of Variation 12.1 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Apparent Terminal Elimination Half-life (t1/2) | 14.8 hours | Geometric Coefficient of Variation 14 |
Secondary
Part A: Apparent Total Clearance (CL/F)
Apparent total clearance following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Apparent Total Clearance (CL/F) | 4.76 liters per hour | Geometric Coefficient of Variation 18.8 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Apparent Total Clearance (CL/F) | 5.00 liters per hour | Geometric Coefficient of Variation 43.2 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Apparent Total Clearance (CL/F) | 4.94 liters per hour | Geometric Coefficient of Variation 36.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Apparent Total Clearance (CL/F) | 4.74 liters per hour | Geometric Coefficient of Variation 18 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Apparent Total Clearance (CL/F) | 4.89 liters per hour | Geometric Coefficient of Variation 28.3 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Apparent Total Clearance (CL/F) | 4.61 liters per hour | Geometric Coefficient of Variation 23.9 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Apparent Total Clearance (CL/F) | 5.52 liters per hour | Geometric Coefficient of Variation 17.9 |
Secondary
Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F)
Apparent volume of distribution during the terminal phase following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 127 liters | Geometric Coefficient of Variation 16.4 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 108 liters | Geometric Coefficient of Variation 26.9 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 112 liters | Geometric Coefficient of Variation 14.2 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 124 liters | Geometric Coefficient of Variation 37.4 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 124 liters | Geometric Coefficient of Variation 31.5 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 109 liters | Geometric Coefficient of Variation 30.3 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | 117 liters | Geometric Coefficient of Variation 20.2 |
Secondary
Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)
Area under concentration-time curve from time 0 extrapolated to infinity following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 210 ng*h/mL | Geometric Coefficient of Variation 18.8 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 600 ng*h/mL | Geometric Coefficient of Variation 43.2 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 607 ng*h/mL | Geometric Coefficient of Variation 36.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 634 ng*h/mL | Geometric Coefficient of Variation 18 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 1230 ng*h/mL | Geometric Coefficient of Variation 28.3 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 2600 ng*h/mL | Geometric Coefficient of Variation 23.9 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 3810 ng*h/mL | Geometric Coefficient of Variation 17.9 |
Comparison: Dose Proportionality Assessment95% CI: [0.882, 1.06]
Comparison: Food Effect Assessment95% CI: [0.926, 1.11]
Comparison: Sex Effect Assessment95% CI: [0.701, 1.59]
Secondary
Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)
Area under curve from time 0 to the time of the last quantifiable concentration following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 198 ng*h/mL | Geometric Coefficient of Variation 18.4 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 575 ng*h/mL | Geometric Coefficient of Variation 40.4 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 578 ng*h/mL | Geometric Coefficient of Variation 33.3 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 600 ng*h/mL | Geometric Coefficient of Variation 18.4 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 1160 ng*h/mL | Geometric Coefficient of Variation 28.4 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 2490 ng*h/mL | Geometric Coefficient of Variation 24 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | 3680 ng*h/mL | Geometric Coefficient of Variation 17.5 |
Comparison: Dose Proportionality Assessment95% CI: [0.891, 1.06]
Comparison: Food Effect Assessment95% CI: [0.905, 1.12]
Comparison: Sex Effect Assessment95% CI: [0.707, 1.54]
Secondary
Part A: Maximum Observed Concentration (Cmax)
Maximum observed concentration following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Maximum Observed Concentration (Cmax) | 11.9 ng/mL | Geometric Coefficient of Variation 30.3 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Maximum Observed Concentration (Cmax) | 31.6 ng/mL | Geometric Coefficient of Variation 27.7 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Maximum Observed Concentration (Cmax) | 30.0 ng/mL | Geometric Coefficient of Variation 16.6 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Maximum Observed Concentration (Cmax) | 38.8 ng/mL | Geometric Coefficient of Variation 14.6 |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Maximum Observed Concentration (Cmax) | 60.3 ng/mL | Geometric Coefficient of Variation 26.5 |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Maximum Observed Concentration (Cmax) | 146 ng/mL | Geometric Coefficient of Variation 16.5 |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Maximum Observed Concentration (Cmax) | 236 ng/mL | Geometric Coefficient of Variation 15.9 |
Comparison: Dose Proportionality Assessment95% CI: [0.909, 1.07]
Comparison: Food Effect Assessment95% CI: [0.824, 1.09]
Comparison: Sex Effect Assessment95% CI: [0.928, 1.62]
Secondary
Part A: Time of the Maximum Observed Concentration (Tmax)
Time of the maximum observed concentration following single oral dose of KRP-A218
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part A: Time of the Maximum Observed Concentration (Tmax) | 3.00 hours |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part A: Time of the Maximum Observed Concentration (Tmax) | 4.00 hours |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part A: Time of the Maximum Observed Concentration (Tmax) | 3.50 hours |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part A: Time of the Maximum Observed Concentration (Tmax) | 4.00 hours |
| Part A: 3 mg KRP-A218 (Fasted Female) | Part A: Time of the Maximum Observed Concentration (Tmax) | 3.50 hours |
| Part A: 6 mg KRP-A218 (Fasted Male) | Part A: Time of the Maximum Observed Concentration (Tmax) | 3.00 hours |
| Part A: 12 mg KRP-A218 (Fasted Male) | Part A: Time of the Maximum Observed Concentration (Tmax) | 3.00 hours |
Secondary
Part B: Apparent Terminal Elimination Half-life (t1/2)
Assessment of the apparent terminal elimination half-life (t1/2)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 1 | 13.0 hours | Geometric Coefficient of Variation 18.8 |
| Part A: Placebo | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 14 | 18.8 hours | Geometric Coefficient of Variation 39.5 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 14 | 16.2 hours | Geometric Coefficient of Variation 22.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 1 | 12.5 hours | Geometric Coefficient of Variation 15.8 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 1 | 11.7 hours | Geometric Coefficient of Variation 12.4 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 14 | 17.6 hours | Geometric Coefficient of Variation 21 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 1 | 12.6 hours | Geometric Coefficient of Variation 16.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Terminal Elimination Half-life (t1/2) | Day 14 | 17.2 hours | Geometric Coefficient of Variation 20.5 |
Secondary
Part B: Apparent Total Clearance (CL/F)
Assessment of the apparent total clearance (CL/F)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Apparent Total Clearance (CL/F) | Day 1 | 5.45 liters per hour | Geometric Coefficient of Variation 18.5 |
| Part A: Placebo | Part B: Apparent Total Clearance (CL/F) | Day 14 | 5.06 liters per hour | Geometric Coefficient of Variation 24.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Total Clearance (CL/F) | Day 14 | 4.92 liters per hour | Geometric Coefficient of Variation 24.5 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Total Clearance (CL/F) | Day 1 | 5.00 liters per hour | Geometric Coefficient of Variation 24.2 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Total Clearance (CL/F) | Day 1 | 5.03 liters per hour | Geometric Coefficient of Variation 42.5 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Total Clearance (CL/F) | Day 14 | 4.90 liters per hour | Geometric Coefficient of Variation 21.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Total Clearance (CL/F) | Day 1 | 4.44 liters per hour | Geometric Coefficient of Variation 34.2 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Total Clearance (CL/F) | Day 14 | 3.99 liters per hour | Geometric Coefficient of Variation 35 |
Secondary
Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F)
Assessment of the apparent volume of distribution during the terminal phase (Vz/F)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 1 | 102 liters | Geometric Coefficient of Variation 13.2 |
| Part A: Placebo | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 14 | 137 liters | Geometric Coefficient of Variation 52.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 14 | 115 liters | Geometric Coefficient of Variation 23.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 1 | 89.9 liters | Geometric Coefficient of Variation 13.8 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 1 | 84.6 liters | Geometric Coefficient of Variation 35.4 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 14 | 124 liters | Geometric Coefficient of Variation 34.1 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 1 | 80.7 liters | Geometric Coefficient of Variation 24 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Apparent Volume of Distribution During the Terminal Phase (Vz/F) | Day 14 | 99.0 liters | Geometric Coefficient of Variation 23 |
Secondary
Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity)
Assessment of the area under concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity)
Time frame: Day 1
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 367 ng*h/mL | Geometric Coefficient of Variation 18.5 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 800 ng*h/mL | Geometric Coefficient of Variation 24.2 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 1590 ng*h/mL | Geometric Coefficient of Variation 42.5 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Area Under Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-infinity) | 2480 ng*h/mL | Geometric Coefficient of Variation 34.2 |
Secondary
Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast)
Assessment of the area under curve from time 0 to the time of the last quantifiable concentration (AUC0-tlast)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 14 | 575 ng*h/mL | Geometric Coefficient of Variation 28.2 |
| Part A: Placebo | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 1 | 253 ng*h/mL | Geometric Coefficient of Variation 13.7 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 1 | 558 ng*h/mL | Geometric Coefficient of Variation 18.7 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 14 | 1170 ng*h/mL | Geometric Coefficient of Variation 29.1 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 1 | 1170 ng*h/mL | Geometric Coefficient of Variation 38.8 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 14 | 2370 ng*h/mL | Geometric Coefficient of Variation 24.7 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 14 | 4050 ng*h/mL | Geometric Coefficient of Variation 43.2 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Area Under Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-tlast) | Day 1 | 1750 ng*h/mL | Geometric Coefficient of Variation 27.5 |
Comparison: Dose Proportionality Assessment. KRP-A218 assessed across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg.~Dose proportionality results for Part B are only for the Day 14 profile (not Day 1).95% CI: [0.945, 1.29]
Secondary
Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ)
Assessment of the area under the concentration-time curve over a dosing interval (AUC0-τ)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 1 | 254 ng*h/mL | Geometric Coefficient of Variation 13.7 |
| Part A: Placebo | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 14 | 395 ng*h/mL | Geometric Coefficient of Variation 24.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 14 | 813 ng*h/mL | Geometric Coefficient of Variation 24.5 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 1 | 560 ng*h/mL | Geometric Coefficient of Variation 18.7 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 1 | 1170 ng*h/mL | Geometric Coefficient of Variation 38.8 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 14 | 1630 ng*h/mL | Geometric Coefficient of Variation 21.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 1 | 1760 ng*h/mL | Geometric Coefficient of Variation 27.5 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Area Under the Concentration-time Curve Over a Dosing Interval (AUC0-τ) | Day 14 | 2760 ng*h/mL | Geometric Coefficient of Variation 35 |
Comparison: Dose Proportionality Assessment. KRP-A218 assessed across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg.~Dose proportionality results for Part B are only for the Day 14 profile (not Day 1).95% CI: [0.966, 1.26]
Secondary
Part B: Maximum Observed Concentration (Cmax)
Assessment of the maximum observed concentration (Cmax)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Maximum Observed Concentration (Cmax) | Day 1 | 20.0 ng/mL | Geometric Coefficient of Variation 14.2 |
| Part A: Placebo | Part B: Maximum Observed Concentration (Cmax) | Day 14 | 29.9 ng/mL | Geometric Coefficient of Variation 20.8 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Maximum Observed Concentration (Cmax) | Day 14 | 60.9 ng/mL | Geometric Coefficient of Variation 23.5 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Maximum Observed Concentration (Cmax) | Day 1 | 44.0 ng/mL | Geometric Coefficient of Variation 14.5 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Maximum Observed Concentration (Cmax) | Day 1 | 99.0 ng/mL | Geometric Coefficient of Variation 32.4 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Maximum Observed Concentration (Cmax) | Day 14 | 121 ng/mL | Geometric Coefficient of Variation 17.7 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Maximum Observed Concentration (Cmax) | Day 1 | 137 ng/mL | Geometric Coefficient of Variation 24.5 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Maximum Observed Concentration (Cmax) | Day 14 | 204 ng/mL | Geometric Coefficient of Variation 28.8 |
Comparison: Dose Proportionality Assessment. KRP-A218 assessed across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg.~Dose proportionality results for Part B are only for the Day 14 profile (not Day 1).95% CI: [0.971, 1.23]
Secondary
Part B: Minimum Observed Concentration (Cmin)
Assessment of the minimum observed concentration (Cmin)
Time frame: Day 14
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Minimum Observed Concentration (Cmin) | 9.09 ng/mL | Geometric Coefficient of Variation 33.1 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Minimum Observed Concentration (Cmin) | 18.5 ng/mL | Geometric Coefficient of Variation 35.3 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Minimum Observed Concentration (Cmin) | 33.0 ng/mL | Geometric Coefficient of Variation 27.9 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Minimum Observed Concentration (Cmin) | 59.6 ng/mL | Geometric Coefficient of Variation 45.1 |
Secondary
Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T)
Observed accumulation ratio based on area under the concentration-time curve over a dosing interval (ARAUC0-T) in Part B
Time frame: Day 14
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T) | 1.56 ratio | Geometric Coefficient of Variation 13.6 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T) | 1.45 ratio | Geometric Coefficient of Variation 14.2 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T) | 1.41 ratio | Geometric Coefficient of Variation 19.1 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Observed Accumulation Ratio Based on Area Under the Concentration-Time Curve Over a Dosing Interval (ARAUC0-T) | 1.57 ratio | Geometric Coefficient of Variation 14.7 |
Secondary
Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax)
Observed accumulation ratio based on maximum observed concentration during the dosing interval (ARCmax) in Part B
Time frame: Day 14
Population: Pharmacokinetic population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax) | 1.49 ratio | Geometric Coefficient of Variation 14 |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax) | 1.38 ratio | Geometric Coefficient of Variation 11.8 |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax) | 1.21 ratio | Geometric Coefficient of Variation 17 |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Observed Accumulation Ratio Based on Maximum Observed Concentration During the Dosing Interval (ARCmax) | 1.49 ratio | Geometric Coefficient of Variation 9.6 |
Secondary
Part B: Time of the Maximum Observed Concentration (Tmax)
Assessment of the time of the maximum observed concentration (Tmax)
Time frame: Days 1 and 14
Population: Pharmacokinetic population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Placebo | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 1 | 3.00 hours |
| Part A: Placebo | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 14 | 3.00 hours |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 14 | 3.50 hours |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 1 | 3.00 hours |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 14 | 4.00 hours |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 1 | 3.00 hours |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 14 | 3.00 hours |
| Part A: 3 mg KRP-A218 (Fed Male: Treatment Period 2) | Part B: Time of the Maximum Observed Concentration (Tmax) | Day 1 | 3.50 hours |
Secondary
Part C: Number of Participants With Adverse Events
A treatment-emergent adverse event (TEAE) was defined as an adverse event that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. Where a subject experienced multiple TEAEs with the same preferred term for the same treatment, this was counted as 1 TEAE for that treatment under the maximum severity recorded.
Time frame: Screening to follow-up (Approximately 7 weeks)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Placebo | Part C: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: Placebo | Part C: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: Placebo | Part C: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: Placebo | Part C: Number of Participants With Adverse Events | Overall TEAEs | 5 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |
| Part A: 1 mg KRP-A218 (Fasted Male) | Part C: Number of Participants With Adverse Events | Overall TEAEs | 3 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part C: Number of Participants With Adverse Events | TEAEs leading to death | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part C: Number of Participants With Adverse Events | TEAEs leading to discontinuation | 0 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part C: Number of Participants With Adverse Events | Overall TEAEs | 6 participants |
| Part A: 3 mg KRP-A218 (Fasted Male: Treatment Period 1) | Part C: Number of Participants With Adverse Events | Serious TEAEs | 0 participants |