Gout
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to assess the effect of food on the bioavailability of febuxostat after a single oral dose of 80 mg febuxostat XR and to evaluate the pharmacokinetics (PK) of febuxostat after single oral doses of 40 and 80 mg febuxostat XR.
Detailed description
The drug being tested in this study is called febuxostat extended- release (XR). This study is evaluating the effect of food on how febuxostat-XR moves throughout the body. This study will also look at the side effects and all safety results in people who took the study drug. This 3-way crossover study will enroll approximately 36 participants. Eligible participants will be randomly (by chance) assigned to one of the 3 treatment sequences at 1:1:1 ratio. Sequence defines the order in which participants receive Regimens A (febuxostat XR 80 mg after a high fat meal), B (febuxostat XR 40 mg after fasting) and C (febuxostat XR 80 mg after fasting): Sequence 1: A, B, C Sequence 2: B, C, A Sequence 3: C, A, B The dose in a period and the dose in the subsequent period will be separated by a minimum 7-day washout interval. This single-centre trial will be conducted in the United States. Participants will make multiple visits to the clinic including three 4-day periods of confinement to the clinic, and will be contacted by telephone 30 days after last dose of study drug for a follow-up assessment. .
Interventions
DRUGFebuxostat XR
Febuxostat XR capsules
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Has an estimated glomerular filtration rate ≥90 mL/min. 2. Weighs at least 50 kg (110 pounds) and has a body mass index (BMI) from 18.0 to 30.0 kg/m\^2, inclusive, at Screening. 3. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from the signing of the informed consent throughout the duration of the study and for 30 days after the last dose. 4. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose. 5. Able to attend all the visits scheduled in the study. 6. Willing to refrain from strenuous exercise from Day -1 until Study Exit (Day 3 of Period 3).
Exclusion criteria
1. Hypersensitivity to Febuxostat or to any of the components of the formulation. 2. Has received any investigational compound within 30 days prior to the first dose of study medication. 3. Has received febuxostat in a previous clinical study or as a therapeutic agent. 4. Has uncontrolled, clinically significant disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results. 5. Has a known hypersensitivity to any xanthine oxidase (XO) inhibitor, xanthine compounds, Febuxostat or any component of the formulation of Febuxostat tablets, or to caffeine. 6. Has a positive urine drug result for drugs of abuse at Screening or Check-in (Day -1 of Period 1). 7. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the Screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study. 8. Is pregnant or lactating or intending to become pregnant before, during, or within 30 days post last dose; or intending to donate ova during such time period. 9. Intends to impregnate others or donate sperm during the course of this study or for 30 days post last dose. 10. Has evidence of current cardiovascular, central nervous system, hepatic, hematopoietic disease, renal dysfunction, metabolic or endocrine dysfunction, serious allergy, asthma, hypoxemia, hypertension, seizures, or allergic skin rash. There is any finding in the participant's medical history, physical examination, or safety laboratory tests giving reasonable suspicion of a disease that would contraindicate taking febuxostat XR, or a similar drug in the same class, or a disease that might interfere with the conduct of the study. This includes, but is not limited to, peptic ulcer disease, seizure disorders, and cardiac arrhythmias. 11. Has current or recent (within 6 months) gastrointestinal disease that would be expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal reflux, peptic ulcer disease, erosive esophagitis, frequent \[more than once per week\] occurrence of heartburn, or any surgical intervention \[eg, cholecystectomy\]). 12. Has a history of cancer, except basal cell carcinoma that has been in remission for at least 5 years prior to Day 1 of Period 1. 13. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or a known history of human immunodeficiency virus infection. 14. Has used nicotine-containing products (including, but not limited to, cigarettes, pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum) within 28 days prior to Check-in (Day -1 of Period 1) or is unwilling to agree to abstain from nicotine-containing products. Cotinine test is positive at Screening or Check-in (Day 1 of Period 1). 15. Has poor peripheral venous access. 16. Has donated or lost 450 mL or more of his or her blood volume (including plasmapheresis) or had a transfusion of any blood product within 30 days prior to Day 1 of Period 1. 17. Has a Screening abnormal (clinically significant) electrocardiogram (ECG). 18. Has abnormal Screening or Day -1 of Period 1 laboratory values that suggest a clinically significant underlying disease or participant with the following lab abnormalities: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \>1.5 x the upper limit of normal.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Participant blood samples were collected pre-dose and following a single oral dose. |
| Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | Day 1 pre-dose and at multiple time points (up to 48 hours) post dose | Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Participant blood samples were collected pre-dose and following a single oral dose. |
| AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose | AUCt is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration. Participant blood samples were collected pre-dose and following a single oral dose. |
| AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose | AUCt is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUCt) Participant blood samples were collected pre-dose and following a single oral dose. |
| AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose | AUCinf is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. Participant blood samples were collected pre-dose and following a single oral dose. |
| AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 40 mg (Regimen B) and Febuxostate XR 80 mg (Regimen C) in Fasted States | Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose | AUCinf is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. Participant blood samples were collected pre-dose and following a single oral dose. |
Countries
United States
Participant flow
Recruitment details
Healthy participants took part in the study at 1 investigative site in the United States from 2 February 2015 to 19 April 2015.
Pre-assignment details
Healthy participants were enrolled equally in 1 of 3 sequences which determined the order of treatment: Regimen A (febuxostat XR 80 mg after high fat meal), B (febuxostat XR 40 mg after fasting) and C (febuxostat XR 80 mg after fasting). Regimens included a single dose on Day 1 followed by a 7-day washout period prior to receiving the next regimen.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Sequence ABC Febuxostat extended release (XR) 80 mg, capsules, orally, once on Day 1 of Period 1 after a high-fat meal, followed by a 7-day washout period, followed by febuxostat XR 40 mg, capsules, orally, once on Day 1 of Period 2 after a 10-hour fast, followed by a 7-day washout period, followed by febuxostat XR 80, capsules, orally, once on Day 1 of Period 3 after a 10-hour fast. | 12 |
| Treatment Sequence BCA Febuxostat XR 40 mg, capsules, orally, once on Day 1 of Period 1 after a 10-hour fast, followed by a 7-day washout period, followed by febuxostat XR 80 mg, capsules, orally, once on Day 1 of Period 2 after a 10-hour fast, followed by a 7-day washout period, followed by Febuxostat XR 80 mg, capsules, orally, once on Day 1 of Period 3 after a high-fat meal. | 12 |
| Treatment Sequence CAB Febuxostat XR 80 mg, capsules, orally, once on Day 1 of Period 1 after a 10-hour fast, followed by a 7-day washout period, followed by febuxostat XR 80 mg, capsules, orally, once on Day 1 of Period 2 after a high-fat meal, followed by a 7-day washout period, followed by febuxostat XR 40 mg, capsules, orally, once on Day 1 of Period 3 after a 10-hour fast. | 12 |
| Total | 36 |
Baseline characteristics
| Characteristic | Treatment Sequence ABC | Total | Treatment Sequence CAB | Treatment Sequence BCA |
|---|---|---|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 8.37 | 31.8 years STANDARD_DEVIATION 7.05 | 29.1 years STANDARD_DEVIATION 5.35 | 35.0 years STANDARD_DEVIATION 6.32 |
| Alcohol Classification Has Never Drunk | 3 participants | 12 participants | 4 participants | 5 participants |
| Alcohol Classification Is a Current Drinker | 7 participants | 18 participants | 6 participants | 5 participants |
| Alcohol Classification Is an Ex-Drinker | 2 participants | 6 participants | 2 participants | 2 participants |
| Body Mass Index (BMI) | 26.21 kg/m^2 STANDARD_DEVIATION 1.88 | 25.67 kg/m^2 STANDARD_DEVIATION 2.376 | 25.03 kg/m^2 STANDARD_DEVIATION 2.878 | 25.76 kg/m^2 STANDARD_DEVIATION 2.321 |
| Estimated Glomerular Filtration Rate (eGFR) Check-in | 131.43 mL/min STANDARD_DEVIATION 25.231 | 133.36 mL/min STANDARD_DEVIATION 19.509 | 135.95 mL/min STANDARD_DEVIATION 19.147 | 132.71 mL/min STANDARD_DEVIATION 13.999 |
| Estimated Glomerular Filtration Rate (eGFR) Screening | 123.38 mL/min STANDARD_DEVIATION 22.449 | 124.88 mL/min STANDARD_DEVIATION 16.92 | 125.87 mL/min STANDARD_DEVIATION 15.28 | 125.41 mL/min STANDARD_DEVIATION 13.025 |
| Female Reproductive Status Female of Childbearing Potential | 5 participants | 15 participants | 7 participants | 3 participants |
| Female Reproductive Status N/A (Participant is Male) | 6 participants | 17 participants | 5 participants | 6 participants |
| Female Reproductive Status Surgically Sterile | 1 participants | 4 participants | 0 participants | 3 participants |
| Height | 167.6 cm STANDARD_DEVIATION 8.27 | 167.6 cm STANDARD_DEVIATION 10.08 | 166.6 cm STANDARD_DEVIATION 12.35 | 168.8 cm STANDARD_DEVIATION 9.98 |
| Race/Ethnicity, Customized Black or African American | 2 participants | 7 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 participants | 16 participants | 5 participants | 6 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 participants | 20 participants | 7 participants | 6 participants |
| Race/Ethnicity, Customized White | 10 participants | 29 participants | 9 participants | 10 participants |
| Region of Enrollment United States | 12 participants | 36 participants | 12 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 19 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 17 Participants | 5 Participants | 6 Participants |
| Smoking Classification Has Never Smoked | 8 participants | 30 participants | 10 participants | 12 participants |
| Smoking Classification Is a Current Smoker | 0 participants | 0 participants | 0 participants | 0 participants |
| Smoking Classification Is an Ex-Smoker | 4 participants | 6 participants | 2 participants | 0 participants |
| Weight | 73.95 kg STANDARD_DEVIATION 10.802 | 72.13 kg STANDARD_DEVIATION 9.335 | 69.10 kg STANDARD_DEVIATION 8.169 | 73.35 kg STANDARD_DEVIATION 8.867 |
| Xanthine/Caffeine Consumption No | 4 participants | 14 participants | 5 participants | 5 participants |
| Xanthine/Caffeine Consumption Yes | 8 participants | 22 participants | 7 participants | 7 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 | 1 / 35 | 3 / 36 | 2 / 36 |
| serious Total, serious adverse events | 0 / 35 | 0 / 36 | 0 / 36 |
Outcome results
Primary
AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 40 mg (Regimen B) and Febuxostate XR 80 mg (Regimen C) in Fasted States
AUCinf is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose
Population: Participants from the PK population, all participants who received study drug and had at least 1 measurable plasma concentration, who received a single dose of study drug in Regimen B and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 40 mg (Regimen B) and Febuxostate XR 80 mg (Regimen C) in Fasted States | 3745.2837 ng*hr/mL | Standard Deviation 1452.71754 |
| C: Febuxostat XR 80 mg (Fasting) | AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 40 mg (Regimen B) and Febuxostate XR 80 mg (Regimen C) in Fasted States | 7970.7990 ng*hr/mL | Standard Deviation 2852.78221 |
Primary
AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States
AUCinf is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose
Population: Participants from the PK population, all participants who received study drug and had at least 1 measurable plasma concentration, who received a single dose of study drug in Regimen A and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 7816.0704 ng*hr/mL | Standard Deviation 2105.40456 |
| C: Febuxostat XR 80 mg (Fasting) | AUCinf: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 8075.5899 ng*hr/mL | Standard Deviation 2826.48142 |
Primary
AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States
AUCt is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUCt) Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose
Population: Participants from the PK population, all participants who received study drug and had at least 1 measurable plasma concentration, who received a single dose of study drug in Regimen B and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | 3646.2021 ng*hr/mL | Standard Deviation 1465.07275 |
| C: Febuxostat XR 80 mg (Fasting) | AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | 7854.2007 ng*hr/mL | Standard Deviation 2985.41297 |
Primary
AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States
AUCt is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration. Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose
Population: Participants from the PK population, all participants who received study drug and had at least 1 measurable plasma concentration, who received a single dose of study drug in Regimen A and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 7605.4147 ng*hr/mL | Standard Deviation 2086.85262 |
| C: Febuxostat XR 80 mg (Fasting) | AUCt: Area Under the Plasma Concentration-Time Curve (AUC) From Time 0 to Time of the Last Quantifiable Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 7687.1220 ng*hr/mL | Standard Deviation 2853.12475 |
Primary
Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple time points (up to 48 hours) post dose
Population: Participants from the PK population, all participants who received study drug and had at least 1 measurable plasma concentration who received a single dose of study drug in Regimen B and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | 754.9167 ng/mL | Standard Deviation 471.4963 |
| C: Febuxostat XR 80 mg (Fasting) | Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 40 mg (Regimen B) and Febuxostat XR 80 mg (Regimen C) in Fasted States | 1562.1389 ng/mL | Standard Deviation 911.65824 |
Primary
Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States
Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Participant blood samples were collected pre-dose and following a single oral dose.
Time frame: Day 1 pre-dose and at multiple timepoints (up to 48 hours) post dose
Population: Participants from the Pharmacokinetic population (PK), all participants who received study drug and had at least 1 measurable plasma concentration, who received a single dose of study drug in Regimen A and C.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Febuxostat XR 80 mg (Fed) | Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 1020.0000 ng/mL | Standard Deviation 398.14171 |
| C: Febuxostat XR 80 mg (Fasting) | Cmax: Maximum Observed Plasma Concentration for Febuxostat XR 80 mg in Fed (Regimen A) and Fasted (Regimen C) States | 1531.6286 ng/mL | Standard Deviation 906.12813 |
Comparison: Relative bioavailability of a single dose of Febuxostat XR 80 mg in the fasted and fed (high-fat meal) states.90% CI: [0.612, 0.847]