Gout
Conditions
Brief summary
This is a Phase 1, randomized, open-label, 4-way crossover pharmacokinetic (PK) and pharmacodynamic (PD) study in healthy adult male subjects designed to assess the relative bioavailability of RDEA3170 2.5 mg tablets administered as a 10 mg dose (2.5 mg × 4 tablets) and of a single RDEA3170 10 mg tablet. This study will also assess the effect of a low-fat and high-fat meal on the PK and PD of RDEA3170 10 mg tablets.
Interventions
DRUGRDEA3170 10 mg
DRUGRDEA3170 2.5 mg
Sponsors
Ardea Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is able to understand the study procedures and the risks involved and is willing to provide written informed consent before the first study-related activity * Subject has a body weight ≥ 50 kg (110 lbs.) and a body mass index ≥ 18 and ≤ 40 kg/m2 * Subject has a Screening serum urate level ≤ 7 mg/dL * Subject is free of any clinically significant disease or medical condition, per the Investigator's judgment
Exclusion criteria
* Subject has a history or suspicion of kidney stones * Subject has undergone major surgery within 3 months prior to Screening * Subject donated blood or experienced significant blood loss (\> 450 mL) within 12 weeks prior to Day 1 or gave a plasma donation within 4 weeks prior to Day 1 * Subject has inadequate venous access or unsuitable veins for repeated venipuncture * Subject has a Screening serum creatinine value above the upper limit of normal during Screening or at Day -2 (Admission) * Subject cannot swallow multiple tablets * Subject is a heavy caffeine drinker * Subject is unwilling to comply with the dietary restrictions of the study * Subject is unable or unwilling to comply with the study requirements or has a situation or condition that, in the opinion of the Investigator, may interfere with participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC∞: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC∞ of RDEA3170 in low-fat fed state. |
| Cmax: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | Cmax of RDEA3170 in low-fat fed state. |
| AUC Last: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC last of RDEA3170 in low-fat fed state. |
| Maximum Observed Plasma Concentration (Cmax) | Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | Cmax of RDEA3170 in fasted condition. |
| Time of Occurrence of Maximum Observed Concentration (Tmax) | Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | Tmax of RDEA3170 following various treatments. |
| Area Under the Concentration-time Curve From Time Zero to the Quantifiable Last Sampling Timepoint (AUC Last) | Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC last of RDEA3170 in fasted condition. |
| Area Under the Concentration-time Curve From 0 to Infinity (AUC∞) | Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC∞ of RDEA3170 the fasted condition. |
| Apparent Terminal Half-life (t1/2) | Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | t1/2 of RDEA3170 following various treatments. |
| Cmax: Effect of High Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | Cmax of RDEA3170 in high-fat fed state. |
| AUC Last: Effect of High Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC last of RDEA3170 in high-fat fed state. |
| AUC∞: Effect of High Fat Meal on the PK of RDEA3170 Tablets | Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose. | AUC∞ of RDEA3170 in high-fat fed state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | 7 weeks. | — |
| Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Day -1: -24, -23, -22, -21, -20, -18, -16, -14, and -12 hours predose. Days 1, 5, 9, and 13: predose (within 30 minutes prior to dosing) and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose. | PD profiles of uric acid from serum and urine. PD parameters were evaluated to assess whether any potential differences in PK for the 2 different tablets resulted in differences in uric acid excretion. |
Countries
United States
Participant flow
Recruitment details
15 subjects were randomized
Pre-assignment details
Fifteen subjects were randomized to 1 of 4 treatment sequences (ABCD, BACD, ABDC, BADC) in a 1:1:1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Sequence ABCD 2.5 mg x 4 tablets qd fasted, 10 mg tablet qd fasted, 10 mg tablet qd fed low-fat, 10 mg tablet qd fed high-fat. | 3 |
| Sequence BACD 10 mg tablet qd fasted, 2.5 mg x 4 tablets qd fasted, 10 mg tablet qd fed low-fat, 10 mg tablet qd fed high-fat | 4 |
| Sequence ABDC 2.5 x 4 mg tablets qd fasted, 10 mg tablet qd fasted, 10 mg tablet qd fed high-fat, 10 mg tablet qd fed low-fat | 4 |
| Sequence BADC 10 mg tablet qd fasted, 2.5 mg x 4 tablets qd fasted, 10 mg tablet qd fed high-fat, 10 mg tablet qd fed low-fat | 4 |
| Total | 15 |
Baseline characteristics
| Characteristic | Sequence ABCD | Sequence BACD | Sequence ABDC | Sequence BADC | Total |
|---|---|---|---|---|---|
| Age, Continuous | 51 Years STANDARD_DEVIATION 9.8 | 39 Years STANDARD_DEVIATION 9.7 | 40 Years STANDARD_DEVIATION 12.3 | 42 Years STANDARD_DEVIATION 16 | 42 Years STANDARD_DEVIATION 11.9 |
| Age, Customized <65 | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 15 Participants |
| Age, Customized >=65 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 4 Participants | 4 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 1 / 15 | 1 / 15 | 3 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Apparent Terminal Half-life (t1/2)
t1/2 of RDEA3170 following various treatments.
Time frame: Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Apparent Terminal Half-life (t1/2) | 16.5 hr |
| Treatment B | Apparent Terminal Half-life (t1/2) | 15.5 hr |
| Treatment C | Apparent Terminal Half-life (t1/2) | 15.4 hr |
| Treatment D | Apparent Terminal Half-life (t1/2) | 16.6 hr |
Primary
Area Under the Concentration-time Curve From 0 to Infinity (AUC∞)
AUC∞ of RDEA3170 the fasted condition.
Time frame: Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Area Under the Concentration-time Curve From 0 to Infinity (AUC∞) | 131 ng·hr/mL |
| Treatment B | Area Under the Concentration-time Curve From 0 to Infinity (AUC∞) | 130 ng·hr/mL |
90% CI: [87.3, 115]Mixed Models Analysis
Primary
Area Under the Concentration-time Curve From Time Zero to the Quantifiable Last Sampling Timepoint (AUC Last)
AUC last of RDEA3170 in fasted condition.
Time frame: Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Area Under the Concentration-time Curve From Time Zero to the Quantifiable Last Sampling Timepoint (AUC Last) | 119 ng·hr/mL |
| Treatment B | Area Under the Concentration-time Curve From Time Zero to the Quantifiable Last Sampling Timepoint (AUC Last) | 114 ng·hr/mL |
90% CI: [85.6, 111]Mixed Models Analysis
Primary
AUC∞: Effect of High Fat Meal on the PK of RDEA3170 Tablets
AUC∞ of RDEA3170 in high-fat fed state.
Time frame: Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | AUC∞: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 130 ng·hr/mL |
| Treatment B | AUC∞: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 173 ng·hr/mL |
90% CI: [114, 156]Mixed Models Analysis
Primary
AUC∞: Effect of Low Fat Meal on the PK of RDEA3170 Tablets
AUC∞ of RDEA3170 in low-fat fed state.
Time frame: Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | AUC∞: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 130 ng·hr/mL |
| Treatment B | AUC∞: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 108 ng·hr/mL |
90% CI: [73.5, 94.7]Mixed Models Analysis
Primary
AUC Last: Effect of High Fat Meal on the PK of RDEA3170 Tablets
AUC last of RDEA3170 in high-fat fed state.
Time frame: Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | AUC Last: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 114 ng·hr/mL |
| Treatment B | AUC Last: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 160 ng·hr/mL |
90% CI: [121, 163]Mixed Models Analysis
Primary
AUC Last: Effect of Low Fat Meal on the PK of RDEA3170 Tablets
AUC last of RDEA3170 in low-fat fed state.
Time frame: Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | AUC Last: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 114 ng·hr/mL |
| Treatment B | AUC Last: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 97.8 ng·hr/mL |
90% CI: [73.9, 98.8]Mixed Models Analysis
Primary
Cmax: Effect of High Fat Meal on the PK of RDEA3170 Tablets
Cmax of RDEA3170 in high-fat fed state.
Time frame: Days 1 to 13 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Cmax: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 14.9 ng/mL |
| Treatment B | Cmax: Effect of High Fat Meal on the PK of RDEA3170 Tablets | 27.2 ng/mL |
90% CI: [144, 230]Mixed Models Analysis
Primary
Cmax: Effect of Low Fat Meal on the PK of RDEA3170 Tablets
Cmax of RDEA3170 in low-fat fed state.
Time frame: Days 1 to 9 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Cmax: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 14.9 ng/mL |
| Treatment B | Cmax: Effect of Low Fat Meal on the PK of RDEA3170 Tablets | 11.8 ng/mL |
90% CI: [66.4, 94.2]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax of RDEA3170 in fasted condition.
Time frame: Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Treatment A | Maximum Observed Plasma Concentration (Cmax) | 14.1 ng/mL |
| Treatment B | Maximum Observed Plasma Concentration (Cmax) | 14.9 ng/mL |
90% CI: [95.2, 120]Mixed Models Analysis
Primary
Time of Occurrence of Maximum Observed Concentration (Tmax)
Tmax of RDEA3170 following various treatments.
Time frame: Days 1 and 5 at predose, 30 minutes postdose, and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 hours postdose.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A | Time of Occurrence of Maximum Observed Concentration (Tmax) | 2.00 hr |
| Treatment B | Time of Occurrence of Maximum Observed Concentration (Tmax) | 2.00 hr |
| Treatment C | Time of Occurrence of Maximum Observed Concentration (Tmax) | 2.00 hr |
| Treatment D | Time of Occurrence of Maximum Observed Concentration (Tmax) | 4.00 hr |
Secondary
Incidence of Treatment-Emergent Adverse Events
Time frame: 7 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment A | Incidence of Treatment-Emergent Adverse Events | 0 Number of Participants |
| Treatment B | Incidence of Treatment-Emergent Adverse Events | 1 Number of Participants |
| Treatment C | Incidence of Treatment-Emergent Adverse Events | 1 Number of Participants |
| Treatment D | Incidence of Treatment-Emergent Adverse Events | 3 Number of Participants |
Secondary
Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine
PD profiles of uric acid from serum and urine. PD parameters were evaluated to assess whether any potential differences in PK for the 2 different tablets resulted in differences in uric acid excretion.
Time frame: Day -1: -24, -23, -22, -21, -20, -18, -16, -14, and -12 hours predose. Days 1, 5, 9, and 13: predose (within 30 minutes prior to dosing) and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment A | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Serum Urate Maximum % Change | -34.4 Percent | Standard Error 2.08 |
| Treatment A | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Urine Uric Acid % Change(0-24h) | 96.6 Percent | Standard Error 12.5 |
| Treatment A | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 170 Percent | Standard Error 19.5 |
| Treatment A | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Fractional Excretion of Uric Acid % Change (0-24h) | 159 Percent | Standard Error 15.1 |
| Treatment B | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Urine Uric Acid % Change(0-24h) | 78.5 Percent | Standard Error 8.38 |
| Treatment B | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 147 Percent | Standard Error 15.6 |
| Treatment B | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Fractional Excretion of Uric Acid % Change (0-24h) | 151 Percent | Standard Error 22 |
| Treatment B | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Serum Urate Maximum % Change | -34.4 Percent | Standard Error 2.27 |
| Treatment C | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 128 Percent | Standard Error 18.9 |
| Treatment C | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Urine Uric Acid % Change(0-24h) | 53.4 Percent | Standard Error 8.85 |
| Treatment C | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Fractional Excretion of Uric Acid % Change (0-24h) | 149 Percent | Standard Error 22.7 |
| Treatment C | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Serum Urate Maximum % Change | -37.3 Percent | Standard Error 1.89 |
| Treatment D | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Fractional Excretion of Uric Acid % Change (0-24h) | 199 Percent | Standard Error 23.2 |
| Treatment D | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Urine Uric Acid % Change(0-24h) | 65.9 Percent | Standard Error 9.7 |
| Treatment D | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Serum Urate Maximum % Change | -49.0 Percent | Standard Error 1.96 |
| Treatment D | Single Dose Pharmacodynamics (PD) Profile of RDEA3170 From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 179 Percent | Standard Error 21.5 |