Chronic Kidney Disease
Conditions
Keywords
3-period, Crossover, URAT1 inhibitor, Xanthine oxidase inhibitor
Brief summary
This study is a single centre, randomised, open-label, single-dose, 5-period, 5-treatment, crossover study in healthy male and female subjects. This study is intended to assess the relative bioavailability between the fixed dose combination (FDC, i.e. verinurad/allopurinol FDC capsule 12/300 mg) and free combination formulations of verinurad (i.e. verinurad prolonged release Hydroxypropyl methylcellulose \[HPMC\] capsule 12 mg) and allopurinol (i.e. allopurinol table 300 mg) in fasted and fed conditions. The study will also assess the relative bioavailability between a formulation only containing verinurad (i.e. verinurad prolonged release gelatin capsule 12 mg) and the FDC capsule.
Detailed description
The study comprises of: * A Screening Period of maximum 28 days; * Five treatment periods during which subjects will be resident from the morning of Day -2 until at least 72 hours after dosing in Treatment Period 5; discharged on the morning of Day 4 of Treatment Period 5; and * A Follow-up Visit 7 to 14 days after the last dosing. Each subject will receive 5 single dose treatments of verinurad and allopurinol or verinurad alone and subject will be involved in the study for 52 to 59 days.
Interventions
DRUGVerinurad prolonged release HPMC capsule
Randomized subjects will receive oral dose of verinurad HPMC capsule.
Randomized subjects will receive oral dose of allopurinol tablet.
DRUGVerinurad/Allopurinol FDC Capsule
Randomized subjects will receive oral dose of Verinurad/Allopurinol FDC capsule.
DRUGVerinurad prolonged release gelatin Capsule
Randomized subjects will receive oral dose of Verinurad gelatin capsule.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Provision of signed and dated, written informed consent prior to any study specific procedures. * Healthy male and female subjects aged 18 to 50 years (inclusive) with suitable veins for cannulation or repeated venepuncture. * Have a body mass index between 18 and 30 kg/m\^2 (inclusive) and weigh at least 50 kg and no more than 100 kg (inclusive). * Females must have a negative pregnancy test at screening and on admission to the unit and must be: 1. not pregnant or currently lactating or breastfeeding. 2. of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria: (i) postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone (FSH) levels in the postmenopausal range (FSH levels \> 40 IU/mL). (ii) documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 3. OR if of childbearing potential must be willing to use an acceptable method of contraception to avoid pregnancy for the entire study period. * Must be able to swallow multiple capsules and tablets.
Exclusion criteria
* History of gout or any clinically significant disease which, in the opinion of the principal investigator (PI), may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study. * Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the first administration of verinurad. * History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs. * Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results as judged by the Investigator at screening and first admission, including: 1. Alanine aminotransferase \> 1.5 x upper limit of normal (ULN), 2. Aspartate aminotransferase \> 1.5 x ULN, 3. Bilirubin (total) \> 1.5 x ULN, 4. Gamma glutamyl transpeptidase \> 1.5 x ULN. * Any clinically significant abnormal findings in vital signs at the Screening Visit and/or admission to the Clinical Unit, including, but not limited to, any of the following: 1. Pulse (resting, supine) \< 50 beats per minute (bpm) or \> 90 bpm, 2. Systolic blood pressure (BP) \< 90 mmHg or \> 140 mmHg and/or diastolic BP \< 50 mmHg or \> 90 mmHg sustained for \> 10 minutes while resting in a supine position. * Any clinically significant abnormalities on 12 lead electrocardiogram (ECG) at the Screening Visit, including, but not limited to any of the following: 1. QTcF \> 450 ms or \< 340 ms or family history of long QT syndrome, 2. Any significant arrhythmia 3. Conduction abnormalities 4. Clinically significant PR (PQ) interval prolongation (\> 240 ms); intermittent second or third degree AV block, or AV dissociation 5. Complete bundle branch block and/or QRS duration \> 120 ms. * Any positive result at the Screening Visit for serum Hepatitis B surface antigen or Anti Hepatitis B core antibody, hepatitis virus C antibody, and human immunodeficiency virus antibody. * Suspicion or known Gilbert's and/or Lesch Nyhan syndrome. * Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI. * Has received another new chemical or biological entity within 30 days or at least 5 half lives of the first administration of verinurad in this study. * Subjects who have previously received verinurad. * Plasma donation within 1 month of screening or any blood donation/loss of more than 500 mL during the 3 months prior to the Screening Visit. * Subjects who are pregnant, lactating or planning to become pregnant. * Hypersensitivity to verinurad, allopurinol or any drug with a similar chemical structure/class to verinurad and/or allopurinol. * Current smokers or those who have smoked or used nicotine products (including e cigarettes) within the 3 months prior to screening. * Excessive intake of caffeine containing drinks or food as judged by the PI. * Positive screen for drugs of abuse or cotinine (nicotine) at the Screening Visit or positive screen for alcohol, drugs of abuse and cotinine on each admission to the study centre. * Use of drugs with enzyme inducing properties within 3 weeks prior to the first administration of verinurad. * Use of any prescribed or non prescribed medication including antacids, analgesics, herbal remedies, megadose vitamins and minerals during the 2 weeks prior to the first administration of verinurad or longer if the medication has a long half life. * Any AstraZeneca, Parexel or study site employee or their close relatives. * Subjects who cannot communicate reliably with the PI and/or is not able to read, speak and understand the German language. * Judgment by the PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements. * Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order. * Subjects with any special dietary restrictions such as subjects that are lactose intolerant or are vegetarians/vegans. * Subject is a carrier of the HLA B\*58:01 allele. * Subject has a positive test result for severe acute respiratory syndrome corona virus (SARS-CoV-2) RT-PCR before randomisation. * Subject has clinical signs and symptoms consistent with Coronavirus disease 2019 (COVID-19), eg, fever, dry cough, dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission. * History of severe COVID-19 (hospitalisation, extracorporeal membrane oxygenation, mechanically ventilated). * Subjects who are regularly exposed to COVID-19 as part of their daily life. * Subjects who have had or are planning to have the COVID-19 vaccination within 4 weeks prior to screening or at any time during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The AUCinf of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters |
| AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The AUClast of verinurad, allopurinol and oxypurinol were assessed in fasted condition as PK parameters |
| Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The Cmax of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The tmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The tlag of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The t½λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| λz: Terminal Elimination Rate Constant | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The CL/F of verinurad and allopurinol were assessed as PK parameters |
| Cmax: Maximum Observed Plasma Drug Concentration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The Cmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The Vz/F of verinurad and allopurinol were assessed as PK parameters |
| Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The Vss/F of verinurad and allopurinol were assessed as PK parameters |
| Emax, CB: Maximum Percentage Change From Baseline (CB) | Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The Emax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter. |
| tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The tEmax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter. |
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | From screening (Day -28 to -3) until follow-up visit (7 to 14 days post final dose) (approximately 52 to 59 days) | The safety of single doses of verinurad and allopurinol were assessed |
| MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The MRTinf of verinurad and allopurinol were assessed as PK parameters |
| AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The AUCinf of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
| AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Day 1, Day 2, Day 3 and Day 4 of each Treatment Period | The AUClast of verinurad, allopurinol and oxypurinol were assessed as PK parameters |
Countries
Germany
Participant flow
Recruitment details
The study was conducted between 13 April 2021 to 15 July 2021.
Pre-assignment details
Subjects who met all the inclusion and none of the exclusion criteria were randomized at single center. The screening period was from Day -28 to Day -3. Informed consent form (ICF) was signed prior to screening procedures. All the study assessments were performed as per the schedule of assessment.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence 12345 Subjects received single-dose treatments of verinurad and allopurinol or verinurad alone on 5 occasions \[Treatment 1: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fasted state; Treatment 2: verinurad/allopurinol FDC capsule, fasted state; Treatment 3: verinurad/allopurinol FDC capsule, fed state; Treatment 4: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fed state; Treatment 5: verinurad prolonged release gelatin capsule, fasted state\] on Day 1 separated by at least 5 days washout between IMP administration. | 5 |
| Treatment Sequence 23451 Subjects received single-dose treatments of verinurad and allopurinol or verinurad alone on 5 occasions \[Treatment 2: verinurad/allopurinol FDC capsule, fasted state; Treatment 3: verinurad/allopurinol FDC capsule, fed state; Treatment 4: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fed state; Treatment 5: verinurad prolonged release gelatin capsule, fasted state; Treatment 1: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fasted state\] on Day 1 separated by at least 5 days washout between IMP administration. | 5 |
| Treatment Sequence 34512 Subjects received single-dose treatments of verinurad and allopurinol or verinurad alone on 5 occasions \[Treatment 3: verinurad/allopurinol FDC capsule, fed state; Treatment 4: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fed state; Treatment 5: verinurad prolonged release gelatin capsule, fasted state; Treatment 1: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fasted state; Treatment 2: verinurad/allopurinol FDC capsule, fasted state\] on Day 1 separated by at least 5 days washout between IMP administration. | 5 |
| Treatment Sequence 45123 Subjects received single-dose treatments of verinurad and allopurinol or verinurad alone on 5 occasions \[Treatment 3: verinurad/allopurinol FDC capsule, fed state; Treatment 4: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fed state; Treatment 5: verinurad prolonged release gelatin capsule, fasted state; Treatment 1: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fasted state; Treatment 2: verinurad/allopurinol FDC capsule, fasted state\] on Day 1 separated by at least 5 days washout between IMP administration. | 5 |
| Treatment Sequence 51234 Subjects received single-dose treatments of verinurad and allopurinol or verinurad alone on 5 occasions \[Treatment 5: verinurad prolonged release gelatin capsule, fasted state; Treatment 1: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fasted state; Treatment 2: verinurad/allopurinol FDC capsule, fasted state; Treatment 3: verinurad/allopurinol FDC capsule, fed state; Treatment 4: verinurad prolonged release HPMC capsule and allopurinol tablet, as a free combination, fed state\] on Day 1 separated by at least 5 days washout between IMP administration. | 5 |
| Total | 25 |
Baseline characteristics
| Characteristic | Total | Treatment Sequence 51234 | Treatment Sequence 45123 | Treatment Sequence 34512 | Treatment Sequence 23451 | Treatment Sequence 12345 |
|---|---|---|---|---|---|---|
| Age, Continuous | 32.6 Years STANDARD_DEVIATION 8 | 38.4 Years STANDARD_DEVIATION 10.6 | 33.0 Years STANDARD_DEVIATION 4.7 | 26.0 Years STANDARD_DEVIATION 5 | 34.2 Years STANDARD_DEVIATION 8 | 31.4 Years STANDARD_DEVIATION 7.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 5 Participants | 4 Participants | 4 Participants | 4 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 22 Participants | 5 Participants | 5 Participants | 5 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 13 Participants | 2 Participants | 5 Participants | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 12 Participants | 3 Participants | 0 Participants | 3 Participants | 4 Participants | 2 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 8 / 25 | 2 / 25 | 2 / 25 | 6 / 25 | 2 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 | 0 / 25 |
Outcome results
Primary
AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition
The AUCinf of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Verinurad | 180.4 hour*nanogram/millilitre | Geometric Coefficient of Variation 48.87 |
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Allopurinol | 4486 hour*nanogram/millilitre | Geometric Coefficient of Variation 37.86 |
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Oxypurinol | 170100 hour*nanogram/millilitre | Geometric Coefficient of Variation 19.07 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Verinurad | 195.2 hour*nanogram/millilitre | Geometric Coefficient of Variation 48.63 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Allopurinol | 4332 hour*nanogram/millilitre | Geometric Coefficient of Variation 46.4 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity in Fasted Condition | Oxypurinol | 167900 hour*nanogram/millilitre | Geometric Coefficient of Variation 24.1 |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [94.13, 124.49]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [90.96, 102.53]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [95.27, 102.36]
Primary
AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition
The AUClast of verinurad, allopurinol and oxypurinol were assessed in fasted condition as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Verinurad | 169.3 hour*nanogram/milliliter | Geometric Coefficient of Variation 47.82 |
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Allopurinol | 4407 hour*nanogram/milliliter | Geometric Coefficient of Variation 37.98 |
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Oxypurinol | 157100 hour*nanogram/milliliter | Geometric Coefficient of Variation 16.84 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Verinurad | 185.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 49.64 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Allopurinol | 4251 hour*nanogram/milliliter | Geometric Coefficient of Variation 46.91 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration in Fasted Condition | Oxypurinol | 153100 hour*nanogram/milliliter | Geometric Coefficient of Variation 21.35 |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [94.55, 126.29]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [90.38, 102.97]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [94.34, 100.73]
Primary
Cmax: Maximum Observed Plasma Drug Concentration in Fasted State
The Cmax of verinurad, allopurinol and oxypurinol were assessed in fasted state as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Verinurad | 26.62 nanogram/millilitre | Geometric Coefficient of Variation 50.71 |
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Allopurinol | 1526 nanogram/millilitre | Geometric Coefficient of Variation 37.98 |
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Oxypurinol | 6376 nanogram/millilitre | Geometric Coefficient of Variation 16.67 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Verinurad | 34.95 nanogram/millilitre | Geometric Coefficient of Variation 61.87 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Allopurinol | 1471 nanogram/millilitre | Geometric Coefficient of Variation 42.92 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration in Fasted State | Oxypurinol | 6066 nanogram/millilitre | Geometric Coefficient of Variation 21.61 |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [107.03, 161.02]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [81.23, 114.39]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [91.08, 99.4]
Secondary
AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity
The AUCinf of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Verinurad | 180.4 hour*nanogram/millilitre | Geometric Coefficient of Variation 48.87 |
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Oxypurinol | 170100 hour*nanogram/millilitre | Geometric Coefficient of Variation 19.07 |
| Treatment 1 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Allopurinol | 4486 hour*nanogram/millilitre | Geometric Coefficient of Variation 37.86 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Allopurinol | 4332 hour*nanogram/millilitre | Geometric Coefficient of Variation 46.4 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Verinurad | 195.2 hour*nanogram/millilitre | Geometric Coefficient of Variation 48.63 |
| Treatment 2 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Oxypurinol | 167900 hour*nanogram/millilitre | Geometric Coefficient of Variation 24.1 |
| Treatment 3 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Allopurinol | 3551 hour*nanogram/millilitre | Geometric Coefficient of Variation 37.17 |
| Treatment 3 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Verinurad | 200.1 hour*nanogram/millilitre | Geometric Coefficient of Variation 54.89 |
| Treatment 3 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Oxypurinol | 153200 hour*nanogram/millilitre | Geometric Coefficient of Variation 24.22 |
| Treatment 4 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Verinurad | 138.4 hour*nanogram/millilitre | Geometric Coefficient of Variation 64.06 |
| Treatment 4 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Oxypurinol | 153300 hour*nanogram/millilitre | Geometric Coefficient of Variation 22.74 |
| Treatment 4 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Allopurinol | 4114 hour*nanogram/millilitre | Geometric Coefficient of Variation 35.79 |
| Treatment 5 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Allopurinol | NA hour*nanogram/millilitre | — |
| Treatment 5 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Verinurad | 187.8 hour*nanogram/millilitre | Geometric Coefficient of Variation 40.22 |
| Treatment 5 | AUCinf: Area Under Plasma Concentration-time Curve From 0 to Infinity | Oxypurinol | NA hour*nanogram/millilitre | — |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [89.12, 117.86]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [125.75, 166.31]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [66.71, 88.23]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [83.64, 110.62]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [83.86, 95.34]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [88.31, 100.4]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [86.37, 97.36]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [88.01, 94.56]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [96.43, 103.61]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [86.95, 93.42]
Secondary
AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration
The AUClast of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Verinurad | 169.3 hour*nanogram/milliliter | Geometric Coefficient of Variation 47.82 |
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Oxypurinol | 157100 hour*nanogram/milliliter | Geometric Coefficient of Variation 16.84 |
| Treatment 1 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Allopurinol | 4407 hour*nanogram/milliliter | Geometric Coefficient of Variation 37.98 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Allopurinol | 4251 hour*nanogram/milliliter | Geometric Coefficient of Variation 46.91 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Verinurad | 185.0 hour*nanogram/milliliter | Geometric Coefficient of Variation 49.64 |
| Treatment 2 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Oxypurinol | 153100 hour*nanogram/milliliter | Geometric Coefficient of Variation 21.35 |
| Treatment 3 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Allopurinol | 3512 hour*nanogram/milliliter | Geometric Coefficient of Variation 45.13 |
| Treatment 3 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Verinurad | 190.3 hour*nanogram/milliliter | Geometric Coefficient of Variation 55.76 |
| Treatment 3 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Oxypurinol | 139200 hour*nanogram/milliliter | Geometric Coefficient of Variation 21.05 |
| Treatment 4 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Verinurad | 129.9 hour*nanogram/milliliter | Geometric Coefficient of Variation 65.65 |
| Treatment 4 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Oxypurinol | 140100 hour*nanogram/milliliter | Geometric Coefficient of Variation 19.57 |
| Treatment 4 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Allopurinol | 4030 hour*nanogram/milliliter | Geometric Coefficient of Variation 35.8 |
| Treatment 5 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Allopurinol | NA hour*nanogram/milliliter | — |
| Treatment 5 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Verinurad | 176.4 hour*nanogram/milliliter | Geometric Coefficient of Variation 39.8 |
| Treatment 5 | AUClast: Area Under Plasma Concentration-time Curve From Zero to the Last Quantifiable Concentration | Oxypurinol | NA hour*nanogram/milliliter | — |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [89.04, 118.93]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [126.82, 169.4]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [66.38, 88.67]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [82.52, 110.23]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [77.38, 88.17]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [81.63, 93.01]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [85.67, 97.61]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [87.98, 93.94]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [96.17, 102.68]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [86.3, 92.15]
Secondary
CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration
The CL/F of verinurad and allopurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Verinurad | 66.54 Liter/hour | Geometric Coefficient of Variation 48.87 |
| Treatment 1 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Allopurinol | 66.88 Liter/hour | Geometric Coefficient of Variation 37.85 |
| Treatment 2 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Verinurad | 61.46 Liter/hour | Geometric Coefficient of Variation 48.63 |
| Treatment 2 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Allopurinol | 69.25 Liter/hour | Geometric Coefficient of Variation 46.4 |
| Treatment 3 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Verinurad | 59.97 Liter/hour | Geometric Coefficient of Variation 54.9 |
| Treatment 3 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Allopurinol | 84.47 Liter/hour | Geometric Coefficient of Variation 37.17 |
| Treatment 4 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Allopurinol | 72.93 Liter/hour | Geometric Coefficient of Variation 35.78 |
| Treatment 4 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Verinurad | 86.73 Liter/hour | Geometric Coefficient of Variation 64.06 |
| Treatment 5 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Verinurad | 63.90 Liter/hour | Geometric Coefficient of Variation 40.22 |
| Treatment 5 | CL/F: Apparent Total Body Clearance of Drug Clearance of Drug From Plasma After Extravascular Administration | Allopurinol | NA Liter/hour | — |
Secondary
Cmax: Maximum Observed Plasma Drug Concentration
The Cmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration | Verinurad | 26.62 nanogram/millilitre | Geometric Coefficient of Variation 50.71 |
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration | Oxypurinol | 6376 nanogram/millilitre | Geometric Coefficient of Variation 16.67 |
| Treatment 1 | Cmax: Maximum Observed Plasma Drug Concentration | Allopurinol | 1526 nanogram/millilitre | Geometric Coefficient of Variation 37.98 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration | Allopurinol | 1471 nanogram/millilitre | Geometric Coefficient of Variation 42.92 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration | Verinurad | 34.95 nanogram/millilitre | Geometric Coefficient of Variation 61.87 |
| Treatment 2 | Cmax: Maximum Observed Plasma Drug Concentration | Oxypurinol | 6066 nanogram/millilitre | Geometric Coefficient of Variation 21.61 |
| Treatment 3 | Cmax: Maximum Observed Plasma Drug Concentration | Allopurinol | 1079 nanogram/millilitre | Geometric Coefficient of Variation 68.87 |
| Treatment 3 | Cmax: Maximum Observed Plasma Drug Concentration | Verinurad | 20.18 nanogram/millilitre | Geometric Coefficient of Variation 70.96 |
| Treatment 3 | Cmax: Maximum Observed Plasma Drug Concentration | Oxypurinol | 5269 nanogram/millilitre | Geometric Coefficient of Variation 19.91 |
| Treatment 4 | Cmax: Maximum Observed Plasma Drug Concentration | Verinurad | 13.86 nanogram/millilitre | Geometric Coefficient of Variation 68.98 |
| Treatment 4 | Cmax: Maximum Observed Plasma Drug Concentration | Oxypurinol | 5709 nanogram/millilitre | Geometric Coefficient of Variation 21.21 |
| Treatment 4 | Cmax: Maximum Observed Plasma Drug Concentration | Allopurinol | 1627 nanogram/millilitre | Geometric Coefficient of Variation 43.71 |
| Treatment 5 | Cmax: Maximum Observed Plasma Drug Concentration | Allopurinol | NA nanogram/millilitre | — |
| Treatment 5 | Cmax: Maximum Observed Plasma Drug Concentration | Verinurad | 35.35 nanogram/millilitre | Geometric Coefficient of Variation 44.84 |
| Treatment 5 | Cmax: Maximum Observed Plasma Drug Concentration | Oxypurinol | NA nanogram/millilitre | — |
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [47.07, 70.81]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [118.66, 178.52]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [42.46, 63.87]
Comparison: Statistical Comparison of Verinurad~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [82.48, 124.08]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [61.81, 87.03]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [55.9, 78.72]
Comparison: Statistical Comparison of Allopurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [89.81, 126.47]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [83.15, 90.74]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [88.35, 96.42]
Comparison: Statistical Comparison of Oxypurinol~Analysis of variance (ANOVA) of log transformed PK parameter with treatment, sequence, period as fixed effects and subject nested within sequence as random effect90% CI: [85.71, 93.54]
Secondary
Emax, CB: Maximum Percentage Change From Baseline (CB)
The Emax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter.
Time frame: Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PD analysis set consisted of all subjects in the safety analysis set who received at least one of the verinurad and allopurinol (or verinurad alone for Treatment 5) doses and who had at least one quantifiable time-matched sUA concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment 1 | Emax, CB: Maximum Percentage Change From Baseline (CB) | -50.44 percentage (%) | Standard Deviation 8.304 |
| Treatment 2 | Emax, CB: Maximum Percentage Change From Baseline (CB) | -53.84 percentage (%) | Standard Deviation 9.947 |
| Treatment 3 | Emax, CB: Maximum Percentage Change From Baseline (CB) | -56.63 percentage (%) | Standard Deviation 9.618 |
| Treatment 4 | Emax, CB: Maximum Percentage Change From Baseline (CB) | -54.43 percentage (%) | Standard Deviation 8.895 |
| Treatment 5 | Emax, CB: Maximum Percentage Change From Baseline (CB) | -38.15 percentage (%) | Standard Deviation 9.724 |
Secondary
MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity
The MRTinf of verinurad and allopurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Verinurad | 18.99 hour | Geometric Coefficient of Variation 41.94 |
| Treatment 1 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Allopurinol | 2.629 hour | Geometric Coefficient of Variation 18.88 |
| Treatment 2 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Verinurad | 15.28 hour | Geometric Coefficient of Variation 43.14 |
| Treatment 2 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Allopurinol | 2.950 hour | Geometric Coefficient of Variation 23.3 |
| Treatment 3 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Verinurad | 18.91 hour | Geometric Coefficient of Variation 40.5 |
| Treatment 3 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Allopurinol | 4.626 hour | Geometric Coefficient of Variation 43.33 |
| Treatment 4 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Allopurinol | 2.827 hour | Geometric Coefficient of Variation 37.87 |
| Treatment 4 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Verinurad | 18.19 hour | Geometric Coefficient of Variation 38.37 |
| Treatment 5 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Verinurad | 15.94 hour | Geometric Coefficient of Variation 52.27 |
| Treatment 5 | MRTinf: Mean Residence Time of the Unchanged Drug in the Systemic Circulation From Zero to Infinity | Allopurinol | NA hour | — |
Secondary
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events
The safety of single doses of verinurad and allopurinol were assessed
Time frame: From screening (Day -28 to -3) until follow-up visit (7 to 14 days post final dose) (approximately 52 to 59 days)
Population: The safety analysis set included all subjects who received at least one dose of IMP and for whom any safety post-dose data were available.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE | 8 Participants |
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE | 0 Participants |
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE leading to discontinuation of IP | 0 Participants |
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related AE | 3 Participants |
| Treatment 1 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related AE | 1 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE | 2 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE leading to discontinuation of IP | 0 Participants |
| Treatment 2 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE | 0 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE leading to discontinuation of IP | 0 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related AE | 1 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE | 2 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE | 0 Participants |
| Treatment 3 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE leading to discontinuation of IP | 0 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE | 0 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related AE | 3 Participants |
| Treatment 4 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE | 6 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related AE | 1 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE with outcome of death | 0 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any SAE | 0 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any possibly related SAE | 0 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE leading to discontinuation of IP | 0 Participants |
| Treatment 5 | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events | Any AE | 2 Participants |
Secondary
t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve
The t½λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Verinurad | 15.57 hour | Geometric Coefficient of Variation 53.19 |
| Treatment 1 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Oxypurinol | 19.06 hour | Geometric Coefficient of Variation 19.81 |
| Treatment 1 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Allopurinol | 1.164 hour | Geometric Coefficient of Variation 21.78 |
| Treatment 2 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Allopurinol | 1.142 hour | Geometric Coefficient of Variation 19.13 |
| Treatment 2 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Verinurad | 14.17 hour | Geometric Coefficient of Variation 58.62 |
| Treatment 2 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Oxypurinol | 20.45 hour | Geometric Coefficient of Variation 22.87 |
| Treatment 3 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Allopurinol | 1.696 hour | Geometric Coefficient of Variation 56.37 |
| Treatment 3 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Verinurad | 13.69 hour | Geometric Coefficient of Variation 57.74 |
| Treatment 3 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Oxypurinol | 20.14 hour | Geometric Coefficient of Variation 23.18 |
| Treatment 4 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Verinurad | 13.77 hour | Geometric Coefficient of Variation 61.38 |
| Treatment 4 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Oxypurinol | 20.21 hour | Geometric Coefficient of Variation 23 |
| Treatment 4 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Allopurinol | 1.085 hour | Geometric Coefficient of Variation 24.91 |
| Treatment 5 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Allopurinol | NA hour | — |
| Treatment 5 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Verinurad | 14.71 hour | Geometric Coefficient of Variation 61.15 |
| Treatment 5 | t½λz: Half-life Associated With Terminal Slope (λz) of Semi-logarithmic Concentration-time Curve | Oxypurinol | NA hour | — |
Secondary
tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB)
The tEmax, CB in serum uric acid (sUA) concentration (time-matched, Day -1) was assessed as PD parameter.
Time frame: Day -1, Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PD analysis set consisted of all subjects in the safety analysis set who received at least one of the verinurad and allopurinol (or verinurad alone for Treatment 5) doses and who had at least one quantifiable time-matched sUA concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment 1 | tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | 8.00 hour |
| Treatment 2 | tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | 6.00 hour |
| Treatment 3 | tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | 12.00 hour |
| Treatment 4 | tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | 12.00 hour |
| Treatment 5 | tEmax, CB: Time of Maximum Percentage CB Change From Baseline (CB) | 12.00 hour |
Secondary
Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma
The tlag of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment 1 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Verinurad | 0.00 hour |
| Treatment 1 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Oxypurinol | 0.00 hour |
| Treatment 1 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Allopurinol | 0.00 hour |
| Treatment 2 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Allopurinol | 0.00 hour |
| Treatment 2 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Verinurad | 0.00 hour |
| Treatment 2 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Oxypurinol | 0.00 hour |
| Treatment 3 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Allopurinol | 1.02 hour |
| Treatment 3 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Verinurad | 1.00 hour |
| Treatment 3 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Oxypurinol | 0.00 hour |
| Treatment 4 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Verinurad | 1.02 hour |
| Treatment 4 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Oxypurinol | 0.00 hour |
| Treatment 4 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Allopurinol | 0.00 hour |
| Treatment 5 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Allopurinol | NA hour |
| Treatment 5 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Verinurad | 0.00 hour |
| Treatment 5 | Tlag: Time Delay Between Drug Administration and First Observed Concentration in Plasma | Oxypurinol | NA hour |
Secondary
Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration
The tmax of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment 1 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Verinurad | 5.00 hour |
| Treatment 1 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Oxypurinol | 4.00 hour |
| Treatment 1 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Allopurinol | 1.50 hour |
| Treatment 2 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Allopurinol | 1.50 hour |
| Treatment 2 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Verinurad | 4.00 hour |
| Treatment 2 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Oxypurinol | 4.00 hour |
| Treatment 3 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Allopurinol | 3.00 hour |
| Treatment 3 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Verinurad | 9.98 hour |
| Treatment 3 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Oxypurinol | 6.02 hour |
| Treatment 4 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Verinurad | 5.03 hour |
| Treatment 4 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Oxypurinol | 4.00 hour |
| Treatment 4 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Allopurinol | 1.50 hour |
| Treatment 5 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Allopurinol | NA hour |
| Treatment 5 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Verinurad | 4.00 hour |
| Treatment 5 | Tmax: Time to Reach Maximum Observed Plasma Concentration Following Drug Administration | Oxypurinol | NA hour |
Secondary
Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration
The Vss/F of verinurad and allopurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Verinurad | 1264 Liter | Geometric Coefficient of Variation 55.42 |
| Treatment 1 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Allopurinol | 175.8 Liter | Geometric Coefficient of Variation 37.01 |
| Treatment 2 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Verinurad | 939.3 Liter | Geometric Coefficient of Variation 62.63 |
| Treatment 2 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Allopurinol | 204.3 Liter | Geometric Coefficient of Variation 38.33 |
| Treatment 3 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Verinurad | 1134 Liter | Geometric Coefficient of Variation 65.96 |
| Treatment 3 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Allopurinol | 390.7 Liter | Geometric Coefficient of Variation 65.33 |
| Treatment 4 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Allopurinol | 206.1 Liter | Geometric Coefficient of Variation 45.73 |
| Treatment 4 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Verinurad | 1578 Liter | Geometric Coefficient of Variation 76.33 |
| Treatment 5 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Verinurad | 1018 Liter | Geometric Coefficient of Variation 50.97 |
| Treatment 5 | Vss/F: Apparent Volume of Distribution at Steady State Following Extravascular Administration | Allopurinol | NA Liter | — |
Secondary
Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration
The Vz/F of verinurad and allopurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Verinurad | 1495 Liter | Geometric Coefficient of Variation 62.63 |
| Treatment 1 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Allopurinol | 112.4 Liter | Geometric Coefficient of Variation 31.38 |
| Treatment 2 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Verinurad | 1256 Liter | Geometric Coefficient of Variation 69.76 |
| Treatment 2 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Allopurinol | 114.2 Liter | Geometric Coefficient of Variation 42.56 |
| Treatment 3 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Verinurad | 1184 Liter | Geometric Coefficient of Variation 74.23 |
| Treatment 3 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Allopurinol | 206.7 Liter | Geometric Coefficient of Variation 80.39 |
| Treatment 4 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Allopurinol | 114.1 Liter | Geometric Coefficient of Variation 31.6 |
| Treatment 4 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Verinurad | 1723 Liter | Geometric Coefficient of Variation 89.59 |
| Treatment 5 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Verinurad | 1356 Liter | Geometric Coefficient of Variation 55.95 |
| Treatment 5 | Vz/F: Apparent Volume of Distribution During Terminal Phase After Extravascular Administration | Allopurinol | NA Liter | — |
Secondary
λz: Terminal Elimination Rate Constant
The λz of verinurad, allopurinol and oxypurinol were assessed as PK parameters
Time frame: Day 1, Day 2, Day 3 and Day 4 of each Treatment Period
Population: The PK analysis set included all subjects in the safety analysis set who received a verinurad + allopurinol (or verinurad alone for Treatment 5) dose and who had at least one quantifiable post-dose plasma concentration.~Here, number analysed in each row signifies the subjects with available data that were analysed for each drug for that outcome measure.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment 1 | λz: Terminal Elimination Rate Constant | Verinurad | 0.04437 per hour | Geometric Coefficient of Variation 55.1 |
| Treatment 1 | λz: Terminal Elimination Rate Constant | Oxypurinol | 0.03653 per hour | Geometric Coefficient of Variation 19.58 |
| Treatment 1 | λz: Terminal Elimination Rate Constant | Allopurinol | 0.5951 per hour | Geometric Coefficient of Variation 21.96 |
| Treatment 2 | λz: Terminal Elimination Rate Constant | Allopurinol | 0.6065 per hour | Geometric Coefficient of Variation 18.98 |
| Treatment 2 | λz: Terminal Elimination Rate Constant | Verinurad | 0.04876 per hour | Geometric Coefficient of Variation 65.26 |
| Treatment 2 | λz: Terminal Elimination Rate Constant | Oxypurinol | 0.03309 per hour | Geometric Coefficient of Variation 24.22 |
| Treatment 3 | λz: Terminal Elimination Rate Constant | Allopurinol | 0.4075 per hour | Geometric Coefficient of Variation 57.03 |
| Treatment 3 | λz: Terminal Elimination Rate Constant | Verinurad | 0.04957 per hour | Geometric Coefficient of Variation 61.83 |
| Treatment 3 | λz: Terminal Elimination Rate Constant | Oxypurinol | 0.03512 per hour | Geometric Coefficient of Variation 23.12 |
| Treatment 4 | λz: Terminal Elimination Rate Constant | Verinurad | 0.05063 per hour | Geometric Coefficient of Variation 57.34 |
| Treatment 4 | λz: Terminal Elimination Rate Constant | Oxypurinol | 0.03425 per hour | Geometric Coefficient of Variation 24.67 |
| Treatment 4 | λz: Terminal Elimination Rate Constant | Allopurinol | 0.6384 per hour | Geometric Coefficient of Variation 25.11 |
| Treatment 5 | λz: Terminal Elimination Rate Constant | Allopurinol | NA per hour | — |
| Treatment 5 | λz: Terminal Elimination Rate Constant | Verinurad | 0.04651 per hour | Geometric Coefficient of Variation 60.92 |
| Treatment 5 | λz: Terminal Elimination Rate Constant | Oxypurinol | NA per hour | — |