Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Danirixin, Healthy, Food effect, Relative Bioavailability, Hydrobromide Salt
Brief summary
This 2-part study will be carried out on healthy elderly subjects to evaluate relative bioavailability of danirixin formulations. Part A will support the selection of the formulation and Part B will assess food effect, bioavailability and pharmacokinetic (PK) profile of selected formulation from Part A. Danirixin is currently administered with food, therefore the investigation of food effect for the selected formulation could potentially enable dosing without food. Approximately 16 subjects will be included in Part A and approximately 24 subjects will be included in Part B. Both parts will include a screening phase, treatment phase with in-between washout period and a follow-up phase.
Interventions
DRUGDanirixin
Danirixin is being developed as a potential anti-inflammatory agent for the treatment of chronic obstructive pulmonary disorder (COPD) and other inflammatory diseases and influenza. Danirixin reference (600 mg) or test formulation (475 or 600 mg or 600 mg with 5 percent HPMC) immediate release tablets will be administered by oral route in a cross-over manner.
DRUGOmeprazole
Omeprazole is used as an antacid. OMP 40 mg delayed-release capsule will be administered by oral route to randomized subjects.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
This will be an open-label study and blinding will not be performed.
Intervention model description
Subjects will receive danirixin reference and test formulations in a cross-over manner.
Eligibility
Sex/Gender
ALL
Age
65 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects must be 65 to 80 years of age inclusive, at the Screening Visit. * Subjects who are healthy, as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring or a subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included if the investigator and the GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce risk factors and will not interfere with the study procedures and objectives. Additionally, laboratory assessments that are specifically listed in the inclusion or
Exclusion criteria
and are outside of the reference range can be repeated once during the screening period. * Body weight \>=50 kilograms (kg) and body mass index (BMI) within the range 19 - 34 kg per meter square (kg/m\^2) (inclusive). * Male or female subjects will be included. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 60 hours after the last dose of study treatment. * Capable of giving signed informed consent. * AST, ALT, alkaline phosphatase and bilirubin \<= 1.5 × upper limit of normal (ULN) (isolated bilirubin \> 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin \< 35 percent). * Resting BP of \<= 160/90 millimeters of mercury (mmHg), irrespective of anti-hypertensive medication status for the subject. * Able to consume the Food and Drug Administration (FDA) defined high fat meal within 30 minutes in each of the four treatment periods where study treatment is administered in a fed state.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the pharmacokinetic (PK) profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Up to 29 days in Part 1 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. |
| Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | Up to 29 days in Part 1 | Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest. |
| Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | Up to 29 days in Part 1 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented. |
| Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | Up to 29 days in Part 1 | Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct bilirubin, creatinine, sodium alanine, aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Terminal Half-life (t1/2) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Terminal Half-life (t1/2) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2 | Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times. |
| Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Up to 52 days in Part 2 | AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant. |
| Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | Up to 52 days in Part 2 | Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest. |
| Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | Up to 52 days in Part 2 | Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented. |
| Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | Up to 52 days in Part 2 | Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate, Aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct, bilirubin, creatinine sodium alanine, Aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine. |
Countries
United States
Participant flow
Recruitment details
This two-part study assessed the relative bioavailability of Danirixin (DNX) tablet formulations along with effect of food and gastric acid secretion suppression on DNX pharmacokinetics. This study was conducted at a single center in the United States from 07-Mar-2018 to 25-Jul-2018.
Pre-assignment details
Danirixin hemihydrate salt tablet formulation manufactured using roller compaction (RC) was compared to test formulations manufactured by direct compression (DC) with an excipient hydroxypropyl methylcellulose (HPMC) to evaluate the most appropriate formulation/dosing regimen. A total of 40 participants were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| DNX 50 mg 600RC/475DC/600DC/600DC-5% HPMC in Fed State Participants received a sequence of the following: single oral dose of 50 milligrams (mg) DNX hydrobromide (HBr) hemihydrate tablet formulation (600 mg tablet manufactured by RC \[600 RC\]) on Day 1 of treatment period 1, a single oral dose of 50 mg DNX HBr hemihydrate tablet formulation (475 mg tablet manufactured by DC \[475 DC\]) on Day 1 of treatment period 2, a single oral dose of 50 mg DNX HBr hemihydrate tablet formulation (600 DC) on Day 1 of treatment period 3 and 50 mg DNX HBr hemihydrate 600 DC tablet formulation with containing 5 percent HPMC on Day 1 of treatment period 4. All the formulations were administered in fed state (with a high fat meal). The treatment periods were separated by a washout period of 5 days. | 8 |
| DNX 50mg 600RC/475DC/600DC/600DC-5% HPMC in Fasted State Participants received a sequence of the following: single oral dose of 50 mg DNX HBr hemihydrate 600 RC on Day 1 of treatment period 1, a single oral dose of 50 mg DNX HBr hemihydrate 475 DC on Day 1 of treatment period 2, a single oral dose 50 mg DNX HBr hemihydrate 600 DC on Day 1 of treatment period 3 and a single oral dose of 50 mg DNX HBr hemihydrate 600 DC with 5 percent HPMC on Day 1 of treatment period 4. All the formulations were administered in fasted state. The treatment periods were separated by a washout period of 5 days. | 8 |
| DNX 50 mg 475 DC Under Fasted/Normal/Fat Meal/ Mono-fat Meal Participants received a sequence of the following: single oral dose of 50 mg DNX HBr hemihydrate 475 DC tablet formulation in fasted state on Day 1 of treatment period 1, a single oral dose of 50 mg DNX HBr hemihydrate 475 DC along with normal meal on Day 1 of treatment period 2, a single oral dose of 50 mg DNX HBr hemihydrate 475 DC along with high fat meal in treatment period 3, followed by a single oral dose of 50 mg DNX HBr monohydrate 475 DC with high fat meal in treatment period 4. The treatment periods were separated by a washout period of 5 days. | 12 |
| DNX 50 mg 475 DC+OMP 40mg Under Fasted/Normal/Fat Meal State Participants received a sequence of the following: single oral dose of 50 mg DNX HBr hemihydrate 475 DC in fasted state along with 40 mg omeprazole (OMP) during treatment period 1, a single oral dose of 50 mg DNX HBr hemihydrate 475 DC and 40 mg OMP along with normal meal in treatment period 2 and a single oral dose of 50 mg DNX HBr hemihydrate 475 DC and 40 mg OMP along with high fat meal in treatment period 3. The treatment periods were separated by a washout period of 5 days. OMP was administered from Day -4 of each treatment period through washout periods. | 12 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part 2, Washout Period 1 (5 Days) | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | DNX 50 mg 600RC/475DC/600DC/600DC-5% HPMC in Fed State | DNX 50mg 600RC/475DC/600DC/600DC-5% HPMC in Fasted State | DNX 50 mg 475 DC Under Fasted/Normal/Fat Meal/ Mono-fat Meal | DNX 50 mg 475 DC+OMP 40mg Under Fasted/Normal/Fat Meal State | Total |
|---|---|---|---|---|---|
| Age, Continuous | 69.4 Years STANDARD_DEVIATION 3.54 | 70.9 Years STANDARD_DEVIATION 4.58 | 71.3 Years STANDARD_DEVIATION 4.14 | 69.4 Years STANDARD_DEVIATION 2.68 | 70.3 Years STANDARD_DEVIATION 3.7 |
| Race/Ethnicity, Customized Black or African American | 1 Count of Participants | 0 Count of Participants | 0 Count of Participants | 2 Count of Participants | 3 Count of Participants |
| Race/Ethnicity, Customized White | 7 Count of Participants | 8 Count of Participants | 12 Count of Participants | 10 Count of Participants | 37 Count of Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 4 Participants | 8 Participants | 22 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 8 Participants | 4 Participants | 18 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 11 | 0 / 12 |
| other Total, other adverse events | 1 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 2 / 8 | 1 / 8 | 1 / 8 | 1 / 8 | 1 / 12 | 1 / 12 | 1 / 12 | 0 / 12 | 0 / 11 | 0 / 11 | 3 / 12 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 12 | 0 / 11 | 0 / 11 | 0 / 12 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the pharmacokinetic (PK) profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK Population includes all participants for whom a PK sample was obtained and analyzed. Only those participants with data available at specified time frame were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 6166.7 Hours*nanograms per milliliter | Geometric Coefficient of Variation 19.2 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 6052.9 Hours*nanograms per milliliter | Geometric Coefficient of Variation 14.18 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 5816.4 Hours*nanograms per milliliter | Geometric Coefficient of Variation 22.99 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 5996.1 Hours*nanograms per milliliter | Geometric Coefficient of Variation 26.31 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 11394.6 Hours*nanograms per milliliter | Geometric Coefficient of Variation 30.07 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 11285.7 Hours*nanograms per milliliter | Geometric Coefficient of Variation 32.72 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 10957.4 Hours*nanograms per milliliter | Geometric Coefficient of Variation 31.55 |
| 600DC 5%HPMC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 1 | 11230.8 Hours*nanograms per milliliter | Geometric Coefficient of Variation 28.21 |
Primary
Maximum Observed Concentration (Cmax) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time frame were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 761.5 Nanograms/milliliter | Geometric Coefficient of Variation 27.22 |
| 475DC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 712.8 Nanograms/milliliter | Geometric Coefficient of Variation 20.53 |
| 600DC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 762.3 Nanograms/milliliter | Geometric Coefficient of Variation 37.23 |
| 600DC 5%HPMC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 659.2 Nanograms/milliliter | Geometric Coefficient of Variation 47.4 |
| 600RC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 2708.2 Nanograms/milliliter | Geometric Coefficient of Variation 26.22 |
| 475DC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 2418.5 Nanograms/milliliter | Geometric Coefficient of Variation 27.78 |
| 600DC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 2607.1 Nanograms/milliliter | Geometric Coefficient of Variation 30.24 |
| 600DC 5%HPMC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 1 | 2511.8 Nanograms/milliliter | Geometric Coefficient of Variation 24.19 |
Primary
Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1
Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented.
Time frame: Up to 29 days in Part 1
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 1 Participants |
| 475DC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 2 Participants |
| 600DC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 2 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 2 Participants |
| 600RC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 2 Participants |
| 475DC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 1 Participants |
| 600DC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 2 Participants |
| 600DC 5%HPMC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 1 | 1 Participants |
Primary
Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Time frame: Up to 29 days in Part 1
Population: Modified Intent-to-treat (mITT) Population includes all randomized participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 600RC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 1 Participants |
| 600RC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 475DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 0 Participants |
| 475DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 600DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 0 Participants |
| 600DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 600RC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 2 Participants |
| 600RC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 475DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 1 Participants |
| 475DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 600DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
| 600DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 1 Participants |
| 600DC 5%HPMC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any AE | 1 Participants |
| 600DC 5%HPMC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events (SAEs) in Part 1 | Any SAE | 0 Participants |
Primary
Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1
Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct bilirubin, creatinine, sodium alanine, aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine.
Time frame: Up to 29 days in Part 1
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 475DC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 600DC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 600RC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 475DC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
| 600DC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 1 Participants |
| 600DC 5%HPMC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 1 | 0 Participants |
Primary
Number of Participants With Vital Signs of Potential Clinical Concern in Part 1
Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest.
Time frame: Up to 29 days in Part 1
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 2 Participants |
| 475DC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 2 Participants |
| 600DC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 2 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 2 Participants |
| 600RC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 0 Participants |
| 475DC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 0 Participants |
| 600DC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 0 Participants |
| 600DC 5%HPMC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 1 | 0 Participants |
Secondary
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 11096.7 Hours*nanograms/milliliter | Geometric Coefficient of Variation 36.64 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 6482.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 37.93 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 6706.6 Hours*nanograms/milliliter | Geometric Coefficient of Variation 28.49 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 6187.1 Hours*nanograms/milliliter | Geometric Coefficient of Variation 30.41 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 12762.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 23.58 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 8681.0 Hours*nanograms/milliliter | Geometric Coefficient of Variation 32.68 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC [0-24]) of Danirixin for Part 2 | 7590.8 Hours*nanograms/milliliter | Geometric Coefficient of Variation 37.96 |
Secondary
Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 4919.5 Hours*nanograms/milliliter | Geometric Coefficient of Variation 27.19 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 4952.0 Hours*nanograms/milliliter | Geometric Coefficient of Variation 18.25 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 4984.8 Hours*nanograms/milliliter | Geometric Coefficient of Variation 24.27 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 4705.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 27.96 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 10744.8 Hours*nanograms/milliliter | Geometric Coefficient of Variation 26.07 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 10419.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 27.78 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 10029.3 Hours*nanograms/milliliter | Geometric Coefficient of Variation 32.19 |
| 600DC 5%HPMC Fasted | Area Under the Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC [0-24]) of Danirixin for Part 1 | 10319.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 26.14 |
Secondary
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 12426.4 Hours*nanograms/milliliter | Geometric Coefficient of Variation 35.85 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 7761.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 41.31 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 8136.7 Hours*nanograms/milliliter | Geometric Coefficient of Variation 32.85 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 7356.4 Hours*nanograms/milliliter | Geometric Coefficient of Variation 34.65 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 14615.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 24.23 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 10185.0 Hours*nanograms/milliliter | Geometric Coefficient of Variation 34.57 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC [0-inf]) of Danirixin for Part 2 | 8782.5 Hours*nanograms/milliliter | Geometric Coefficient of Variation 45.73 |
Secondary
Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 5515.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 24.54 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 5573.6 Hours*nanograms/milliliter | Geometric Coefficient of Variation 17.65 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 5524.7 Hours*nanograms/milliliter | Geometric Coefficient of Variation 22.15 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 5287.0 Hours*nanograms/milliliter | Geometric Coefficient of Variation 28.27 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 11480.1 Hours*nanograms/milliliter | Geometric Coefficient of Variation 28.07 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 10977.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 30.52 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 10636.5 Hours*nanograms/milliliter | Geometric Coefficient of Variation 32.09 |
| 600DC 5%HPMC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 1 | 11015.8 Hours*nanograms/milliliter | Geometric Coefficient of Variation 28.35 |
Secondary
Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 12026.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 37 |
| 475DC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 7484.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 39.37 |
| 600DC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 7757.2 Hours*nanograms/milliliter | Geometric Coefficient of Variation 31.77 |
| 600DC 5%HPMC High Fat | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 6986.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 32.54 |
| 600RC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 12903.9 Hours*nanograms/milliliter | Geometric Coefficient of Variation 37.02 |
| 475DC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 9023.8 Hours*nanograms/milliliter | Geometric Coefficient of Variation 42.46 |
| 600DC Fasted | Area Under the Concentration-time Curve From Time 0 to t (AUC [0-t]) of Danirixin for Part 2 | 7885.4 Hours*nanograms/milliliter | Geometric Coefficient of Variation 46.3 |
Secondary
Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.000 Hours | Geometric Coefficient of Variation 0 |
| 475DC High Fat | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.283 Hours | Geometric Coefficient of Variation 0.3554 |
| 600DC High Fat | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.641 Hours | Geometric Coefficient of Variation 0.4405 |
| 600DC 5%HPMC High Fat | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.386 Hours | Geometric Coefficient of Variation 0.4922 |
| 600RC Fasted | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.000 Hours | Geometric Coefficient of Variation 0 |
| 475DC Fasted | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.423 Hours | Geometric Coefficient of Variation 0.3097 |
| 600DC Fasted | Lag Time Before Observable Concentration (Tlag) of Danirixin for Part 2 | 0.370 Hours | Geometric Coefficient of Variation 0.6461 |
Secondary
Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.323 Hours | Standard Deviation 0.3812 |
| 475DC High Fat | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.383 Hours | Standard Deviation 0.5917 |
| 600DC High Fat | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.383 Hours | Standard Deviation 0.5918 |
| 600DC 5%HPMC High Fat | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.511 Hours | Standard Deviation 0.6661 |
| 600RC Fasted | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.000 Hours | Standard Deviation 0 |
| 475DC Fasted | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.065 Hours | Standard Deviation 0.183 |
| 600DC Fasted | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.000 Hours | Standard Deviation 0 |
| 600DC 5%HPMC Fasted | Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of Danirixin for Part 1 | 0.000 Hours | Standard Deviation 0 |
Secondary
Maximum Observed Concentration (Cmax) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 2317.4 Nanograms/milliliter | Geometric Coefficient of Variation 44.9 |
| 475DC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 989.9 Nanograms/milliliter | Geometric Coefficient of Variation 47.91 |
| 600DC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 969.9 Nanograms/milliliter | Geometric Coefficient of Variation 37.8 |
| 600DC 5%HPMC High Fat | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 1019.8 Nanograms/milliliter | Geometric Coefficient of Variation 38.9 |
| 600RC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 2292.5 Nanograms/milliliter | Geometric Coefficient of Variation 43.18 |
| 475DC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 1389.7 Nanograms/milliliter | Geometric Coefficient of Variation 43.59 |
| 600DC Fasted | Maximum Observed Concentration (Cmax) of Danirixin for Part 2 | 1132.5 Nanograms/milliliter | Geometric Coefficient of Variation 35.26 |
Secondary
Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2
Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented.
Time frame: Up to 52 days in Part 2
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 1 Participants |
| 475DC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 2 Participants |
| 600DC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 1 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 3 Participants |
| 600RC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 1 Participants |
| 475DC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 2 Participants |
| 600DC Fasted | Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern in Part 2 | 2 Participants |
Secondary
Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2
AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant.
Time frame: Up to 52 days in Part 2
Population: mITT Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 600RC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 1 Participants |
| 600RC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 475DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 1 Participants |
| 475DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 600DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 1 Participants |
| 600DC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 600RC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 0 Participants |
| 600RC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 475DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 0 Participants |
| 475DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
| 600DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any AE | 3 Participants |
| 600DC Fasted | Number of Participants With Any Adverse Event (AE) and Serious Adverse Events in Part 2 | Any SAE | 0 Participants |
Secondary
Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2
Hematology parameters included platelet count, RBC Count, hemoglobin, hematocrit, MCV, MCH, %Reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils, basophils. Clinical chemistry parameters included potassium aspartate, Aminotransferase(AST)/Serum Glutamic-Oxaloacetic Transaminase (SGOT), total and direct, bilirubin, creatinine sodium alanine, Aminotransferase, (ALT)/ Serum Glutamic-Pyruvic, Transaminase (SGPT), total protein, fasting glucose, calcium, alkaline phosphatase and albumin. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine.
Time frame: Up to 52 days in Part 2
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 475DC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 600DC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 600RC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 475DC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 0 Participants |
| 600DC Fasted | Number of Participants With Laboratory Values of Potential Clinical Concern in Part 2 | 1 Participants |
Secondary
Number of Participants With Vital Signs of Potential Clinical Concern in Part 2
Vital signs included systolic and diastolic blood pressure, temperature, respiratory rate and pulse rate were measured with participants in semi-supine position after 5 minutes rest.
Time frame: Up to 52 days in Part 2
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 600RC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 2 Participants |
| 475DC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 3 Participants |
| 600DC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 4 Participants |
| 600DC 5%HPMC High Fat | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 4 Participants |
| 600RC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 4 Participants |
| 475DC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 3 Participants |
| 600DC Fasted | Number of Participants With Vital Signs of Potential Clinical Concern in Part 2 | 4 Participants |
Secondary
Terminal Half-life (t1/2) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 1 | 9.638 Hours | Geometric Coefficient of Variation 17.6 |
| 475DC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 1 | 10.904 Hours | Geometric Coefficient of Variation 19.33 |
| 600DC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 1 | 8.916 Hours | Geometric Coefficient of Variation 29.74 |
| 600DC 5%HPMC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 1 | 9.888 Hours | Geometric Coefficient of Variation 26.18 |
| 600RC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 1 | 8.298 Hours | Geometric Coefficient of Variation 36.18 |
| 475DC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 1 | 9.498 Hours | Geometric Coefficient of Variation 26.76 |
| 600DC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 1 | 9.391 Hours | Geometric Coefficient of Variation 45.4 |
| 600DC 5%HPMC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 1 | 9.107 Hours | Geometric Coefficient of Variation 29.56 |
Secondary
Terminal Half-life (t1/2) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 2 | 10.647 Hours | Geometric Coefficient of Variation 26.8 |
| 475DC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 2 | 11.424 Hours | Geometric Coefficient of Variation 21.51 |
| 600DC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 2 | 11.484 Hours | Geometric Coefficient of Variation 11.21 |
| 600DC 5%HPMC High Fat | Terminal Half-life (t1/2) of Danirixin for Part 2 | 11.652 Hours | Geometric Coefficient of Variation 20.01 |
| 600RC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 2 | 11.304 Hours | Geometric Coefficient of Variation 15.02 |
| 475DC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 2 | 10.913 Hours | Geometric Coefficient of Variation 24.37 |
| 600DC Fasted | Terminal Half-life (t1/2) of Danirixin for Part 2 | 8.975 Hours | Geometric Coefficient of Variation 33.78 |
Secondary
Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 47.660 Hours | Standard Deviation 0.2178 |
| 475DC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 47.587 Hours | Standard Deviation 0.22 |
| 600DC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 44.657 Hours | Standard Deviation 8.3551 |
| 600DC 5%HPMC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 44.757 Hours | Standard Deviation 8.3813 |
| 600RC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 44.372 Hours | Standard Deviation 8.973 |
| 475DC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 41.789 Hours | Standard Deviation 10.9667 |
| 600DC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 41.699 Hours | Standard Deviation 10.9179 |
| 600DC 5%HPMC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 1 | 44.531 Hours | Standard Deviation 8.3335 |
Secondary
Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 45.139 Hours | Geometric Coefficient of Variation 6.6767 |
| 475DC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 47.144 Hours | Geometric Coefficient of Variation 0.444 |
| 600DC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 47.200 Hours | Geometric Coefficient of Variation 0.4262 |
| 600DC 5%HPMC High Fat | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 46.741 Hours | Geometric Coefficient of Variation 0.4843 |
| 600RC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 45.217 Hours | Geometric Coefficient of Variation 7.0764 |
| 475DC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 45.242 Hours | Geometric Coefficient of Variation 7.0723 |
| 600DC Fasted | Time to Last Quantifiable Concentration (Tlast) of the Blood Concentration of Danirixin for Part 2 | 40.869 Hours | Geometric Coefficient of Variation 10.8896 |
Secondary
Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 2
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 1.271 Hours | Geometric Coefficient of Variation 0.3374 |
| 475DC High Fat | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 3.749 Hours | Geometric Coefficient of Variation 0.6458 |
| 600DC High Fat | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 4.150 Hours | Geometric Coefficient of Variation 1.5008 |
| 600DC 5%HPMC High Fat | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 3.355 Hours | Geometric Coefficient of Variation 1.3724 |
| 600RC Fasted | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 1.978 Hours | Geometric Coefficient of Variation 0.877 |
| 475DC Fasted | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 2.887 Hours | Geometric Coefficient of Variation 0.7802 |
| 600DC Fasted | Time to Maximum Observed Concentration (Tmax) of Danirixin for Part 2 | 3.752 Hours | Geometric Coefficient of Variation 1.7384 |
Secondary
Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1
Blood samples were collected at the indicated time points after administration of study treatment to investigate the PK profile of Danirixin. PK parameters were calculated by standard non-compartmental analysis using WinNonlin based on actual sampling times.
Time frame: Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours in Part 1
Population: PK population. Only those participants with data available at specified time points were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 600RC High Fat | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 3.897 Hours | Standard Deviation 0.9894 |
| 475DC High Fat | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 3.653 Hours | Standard Deviation 0.5089 |
| 600DC High Fat | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 3.585 Hours | Standard Deviation 1.2942 |
| 600DC 5%HPMC High Fat | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 4.158 Hours | Standard Deviation 1.3556 |
| 600RC Fasted | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 1.165 Hours | Standard Deviation 0.3794 |
| 475DC Fasted | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 1.331 Hours | Standard Deviation 0.7536 |
| 600DC Fasted | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 1.214 Hours | Standard Deviation 0.2669 |
| 600DC 5%HPMC Fasted | Time to Occurrence of Cmax (Tmax) of Danirixin for Part 1 | 1.342 Hours | Standard Deviation 0.3768 |