Gout
Conditions
Brief summary
This is a Phase 1b, randomized, open-label, drug-drug interaction study in adult male subjects with gout. It is designed to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of RDEA3170 or allopurinol alone and in combination in the fed state.
Interventions
DRUGRDEA3170 10 mg
Sponsors
Ardea Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subject meets one or more criteria for the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout. * Subject has a body weight ≥ 50 kg (110 lbs.) and a body mass index ≥ 18 and ≤ 45 kg/m2. * Subject has a Screening serum urate level ≥ 8 mg/dL and ≤ 10 mg/dL * Subject is free of any clinically significant disease or medical condition, per the Investigator's judgment.
Exclusion criteria
* Subject is unable to take colchicine for gout flare prophylaxis. * Subject has a history or suspicion of kidney stones. * Subject has an estimated creatinine clearance \< 60 mL/min calculated by the Cockcroft-Gault formula using ideal body weight at Screening prior to Day -2. * Subject is on unstable doses of chronic medications. Subjects taking medications for chronic medical conditions must be on stable doses during the course of the study, including the Screening period. Dose adjustments are allowed if deemed medically necessary by the investigator and following discussion with the medical monitor * Chronic and stable doses of losartan, fenofibrate, guaifenesin, and sodium-glucose linked transporter-2 inhibitors are permitted if the dose is stable for at least 14 days prior to study medication dosing. * 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 |
|---|---|---|
| Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | 22 days | — |
| Maximum Observed Plasma Concentration (Cmax) | 22 days | Cmax of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170 |
| Time of Occurrence of Maximum Observed Concentration (Tmax) | 22 days | Tmax of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination |
| Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 22 days | AUC 0-24 of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170 |
| Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 22 days | AUC last of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170 |
| Apparent Terminal Half-life (t1/2) | 22 days | t1/2 of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination |
| Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 22 days | Ae0-24 of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170 |
| Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 22 days | CLR0-24 of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination |
Secondary
| Measure | Time frame |
|---|---|
| Incidence of Treatment-Emergent Adverse Events | 22 days |
Countries
United States
Participant flow
Recruitment details
12 subjects were randomized
Pre-assignment details
Twelve subjects were randomized to 1 of 2 treatment sequences (Sequence A or B) in a 1:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A Days 1 to 7: 10 mg once daily (qd) RDEA3170; Days 8 to 14: 10 mg qd RDEA3170 + 300 mg qd allopurinol; Days 15 to 21: 300 mg qd allopurinol | 6 |
| Sequence B Days 1 to 7: 300 mg qd allopurinol; Days 8 to 14: 10 mg qd RDEA3170 + 300 mg qd allopurinol; Days 15 to 21: 10 mg qd RDEA3170 | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Sequence A | Sequence B | Total |
|---|---|---|---|
| Age, Continuous | 53 Years STANDARD_DEVIATION 10.1 | 49 Years STANDARD_DEVIATION 10.4 | 51 Years STANDARD_DEVIATION 10 |
| Age, Customized <65 | 6 Participants | 6 Participants | 12 Participants |
| Age, Customized >=65 | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 12 | 1 / 12 | 3 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
Primary
Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24)
Ae0-24 of RDEA3170 Alone and In Combination with Allopurinol
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 66.8 ug |
| Allopurinol: RDEA3170 + Allopurinol | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 67.2 ug |
95% CI: [86.7, 117]Mixed Models Analysis
Primary
Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24)
Ae0-24 of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 25.4 mg |
| Allopurinol: RDEA3170 + Allopurinol | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 22.7 mg |
| Oxypurinol: Allopurinol Alone | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 231 mg |
| Oxypurinol: RDEA3170 + Allopurinol | Amount Excreted in Urine as Unchanged Drug or Metabolite (Ae0-24) | 275 mg |
90% CI: [81.8, 98]Mixed Models Analysis
90% CI: [114, 125]Mixed Models Analysis
Primary
Apparent Terminal Half-life (t1/2)
t1/2 of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Apparent Terminal Half-life (t1/2) | 1.06 hr |
| Allopurinol: RDEA3170 + Allopurinol | Apparent Terminal Half-life (t1/2) | 0.992 hr |
| Oxypurinol: Allopurinol Alone | Apparent Terminal Half-life (t1/2) | 43.2 hr |
| Oxypurinol: RDEA3170 + Allopurinol | Apparent Terminal Half-life (t1/2) | 29.1 hr |
| RDEA3170: RDEA3170 Alone | Apparent Terminal Half-life (t1/2) | 11.5 hr |
| RDEA3170: RDEA3170 + Allopurinol | Apparent Terminal Half-life (t1/2) | 12.5 hr |
Primary
Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last)
AUC last of RDEA3170 Alone and In Combination with Allopurinol
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 120 ng·hr/mL |
| Allopurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 115 ng·hr/mL |
95% CI: [88.4, 104]Mixed Models Analysis
Primary
Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last)
AUC last of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 3.50 μg·hr/mL |
| Allopurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 3.61 μg·hr/mL |
| Oxypurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 255 μg·hr/mL |
| Oxypurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero to the Last Quantifiable Sampling Timepoint (AUC Last) | 157 μg·hr/mL |
90% CI: [94.9, 112]Mixed Models Analysis
90% CI: [58.1, 65.7]Mixed Models Analysis
Primary
Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24)
AUC 0-24 of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 3.69 μg·hr/mL |
| Allopurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 3.68 μg·hr/mL |
| Oxypurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 255 μg·hr/mL |
| Oxypurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 157 μg·hr/mL |
| RDEA3170: RDEA3170 Alone | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 115 μg·hr/mL |
90% CI: [93.3, 111]Mixed Models Analysis
90% CI: [58.1, 65.7]Mixed Models Analysis
90% CI: [88.4, 104]Mixed Models Analysis
Primary
Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24)
AUC 0-24 of RDEA3170 Alone and In Combination with Allopurinol
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 120 μg*hr/mL |
| Allopurinol: RDEA3170 + Allopurinol | Area Under the Concentration-time Curve From Time Zero up to 24 Hours Postdose (AUC 0-24) | 115 μg*hr/mL |
95% CI: [88.4, 104]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax of RDEA3170 Alone and In Combination with Allopurinol
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Maximum Observed Plasma Concentration (Cmax) | 14.6 ng/mL |
| Allopurinol: RDEA3170 + Allopurinol | Maximum Observed Plasma Concentration (Cmax) | 14.5 ng/mL |
95% CI: [87.7, 111]Mixed Models Analysis
Primary
Maximum Observed Plasma Concentration (Cmax)
Cmax of Allopurinol/Oxypurinol Alone and In Combination with RDEA3170
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Maximum Observed Plasma Concentration (Cmax) | 1.13 μg/mL |
| Allopurinol: RDEA3170 + Allopurinol | Maximum Observed Plasma Concentration (Cmax) | 1.51 μg/mL |
| Oxypurinol: Allopurinol Alone | Maximum Observed Plasma Concentration (Cmax) | 12.8 μg/mL |
| Oxypurinol: RDEA3170 + Allopurinol | Maximum Observed Plasma Concentration (Cmax) | 8.68 μg/mL |
90% CI: [111, 159]Mixed Models Analysis
90% CI: [65.2, 70.7]Mixed Models Analysis
Primary
Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine
Time frame: 22 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Allopurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Serum Urate Maximum % Change | -50.5 Percentage (%) | Standard Error 2.43 |
| Allopurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Urine Uric Acid % Change (0-24h) | 9.88 Percentage (%) | Standard Error 7.61 |
| Allopurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 122 Percentage (%) | Standard Error 46.8 |
| Allopurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Fract. Excretion of Uric Acid % Change (0-24h) | 77.4 Percentage (%) | Standard Error 18 |
| Allopurinol: RDEA3170 + Allopurinol | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Fract. Excretion of Uric Acid % Change (0-24h) | 78.4 Percentage (%) | Standard Error 21.9 |
| Allopurinol: RDEA3170 + Allopurinol | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Serum Urate Maximum % Change | -65.2 Percentage (%) | Standard Error 1.57 |
| Allopurinol: RDEA3170 + Allopurinol | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | 125 Percentage (%) | Standard Error 42.2 |
| Allopurinol: RDEA3170 + Allopurinol | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Urine Uric Acid % Change (0-24h) | -21.6 Percentage (%) | Standard Error 5.58 |
| Oxypurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Fract. Excretion of Uric Acid % Change (0-24h) | -12.0 Percentage (%) | Standard Error 5.46 |
| Oxypurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Urine Uric Acid % Change (0-24h) | -47.4 Percentage (%) | Standard Error 2.67 |
| Oxypurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Renal Clearance of Uric Acid % Change (0-24h) | -8.50 Percentage (%) | Standard Error 6.04 |
| Oxypurinol: Allopurinol Alone | Pharmacodynamics (PD) Profile of Uric Acid From Serum and Urine | Serum Urate Maximum % Change | -43.0 Percentage (%) | Standard Error 1.57 |
Primary
Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24)
CLR0-24 of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination
Time frame: 22 days
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 120 mL/min |
| Allopurinol: RDEA3170 + Allopurinol | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 103 mL/min |
| Oxypurinol: Allopurinol Alone | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 15.1 mL/min |
| Oxypurinol: RDEA3170 + Allopurinol | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 29.2 mL/min |
| RDEA3170: RDEA3170 Alone | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 9.28 mL/min |
| RDEA3170: RDEA3170 + Allopurinol | Renal Clearance of the Drug From Time Zero up to 24 Hours Postdose (CRL0-24) | 9.75 mL/min |
90% CI: [79.3, 96.6]Mixed Models Analysis
90% CI: [177, 210]Mixed Models Analysis
90% CI: [94.4, 117]Mixed Models Analysis
Primary
Time of Occurrence of Maximum Observed Concentration (Tmax)
Tmax of Allopurinol/Oxypurinol and RDEA3170 Alone and In Combination
Time frame: 22 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Allopurinol: Allopurinol Alone | Time of Occurrence of Maximum Observed Concentration (Tmax) | 1.50 hr |
| Allopurinol: RDEA3170 + Allopurinol | Time of Occurrence of Maximum Observed Concentration (Tmax) | 1.25 hr |
| Oxypurinol: Allopurinol Alone | Time of Occurrence of Maximum Observed Concentration (Tmax) | 4.00 hr |
| Oxypurinol: RDEA3170 + Allopurinol | Time of Occurrence of Maximum Observed Concentration (Tmax) | 3.50 hr |
| RDEA3170: RDEA3170 Alone | Time of Occurrence of Maximum Observed Concentration (Tmax) | 3.00 hr |
| RDEA3170: RDEA3170 + Allopurinol | Time of Occurrence of Maximum Observed Concentration (Tmax) | 3.00 hr |
Secondary
Incidence of Treatment-Emergent Adverse Events
Time frame: 22 days
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Allopurinol: Allopurinol Alone | Incidence of Treatment-Emergent Adverse Events | 2 Number of participants | 2.43 |
| Allopurinol: RDEA3170 + Allopurinol | Incidence of Treatment-Emergent Adverse Events | 1 Number of participants | 1.57 |
| Oxypurinol: Allopurinol Alone | Incidence of Treatment-Emergent Adverse Events | 3 Number of participants | 1.57 |