Healthy
Conditions
Brief summary
The purpose of this study is to assess the effects of food on the amount of urate in the body after a single oral dose of inosine.
Detailed description
Eighteen (18) eligible healthy male subjects will be randomly assigned to two groups with 9 subjects per group to receive a single oral dose of 1000 mg inosine with or without food on day 1 after an overnight fast. Subjects who receive inosine with food on day 1 will receive a second dose of inosine without food on day 8 after an overnight fast. Subjects who receive inosine without food on day 1 after an overnight fast will receive a second dose of inosine with food on day 8 after an overnight fast. Subjects will be admitted to the clinic before dinner on days 0 and 7, the days before dosing, and will stay in the clinic for 48-h post-dose. During the clinic stay, blood samples will be taken for urate measurements.
Interventions
DRUGInosine
Inosine, 1000 mg
Sponsors
Michael J. Fox Foundation for Parkinson's Research
The Parkinson Alliance
Michael Alan Schwarzschild
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male subjects between the ages of 18 and 65 years 2. Body-mass index between 18.0 kg/m2 and 32.0 kg/m2 3. If not surgically sterile, willing to refrain from donating sperm and willing to use appropriate birth control when engaging in sexual intercourse for a period of 90 days following the last dose of the study medication 4. Serum urate \< 6.1 mg/dL (approximately 360 μM) at screening 5. Non-smokers for at least 6 months prior to screening 6. Adequate venous access at multiple sites in both arms
Exclusion criteria
1. History of alcohol or drug dependence in the past 2 years 2. Had 400 mL of whole blood collection within four months or 200 mL of whole blood collection or who had blood component collection within one month of the screening test 3. Used prescription or over-the-counter (OTC) drugs within 14 days prior to screening 4. Used vitamin preparations or supplements (including St. John's Wort and ginseng) within 28 days prior to the screening test 5. Not willing to refrain from alcohol, grapefruit, grapefruit juice or related products, caffeine consumption (including chocolate), and strenuous exercise within 72 h prior to day 1 and through the end of the PK study 6. Treated with an investigational drug within 30 days or 7 half-lives of the investigational drug, whichever is longer, prior to the first dose of study drug 7. Previously received inosine supplement within three months from the screening or subjects who have had any inosine and suffered an adverse reaction due to it 8. Known HIV disease 9. Had a febrile illness within 5 days prior to the first dose of study medication 10. Vaccinated within 30 days prior to the first dose of medication 11. Has gout or a history or suspicion of kidney stones 12. Determined by the investigator or sub-investigator to be unsuitable for participating in the study based on medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Corrected T1/2: Baseline Corrected Apparent Terminal Half-life | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). |
| Baseline Corrected AUC (0-inf): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Infinity | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose | Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). |
| Baseline Corrected Tmax: Baseline Corrected Time of Maximum Serum Concentration | -12 to 0 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose | Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). |
| Cmax: Maximum Observed Serum Urate Concentration | -12 to 0 hrs pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hrs post-dose | — |
| AUC (0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Plasma Concentration) | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | — |
| AUC (0-inf): Area Under the Serum Concentration-time Curve From Time 0 to Infinity | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | — |
| Tmax: Time of Maximum Serum Concentration | -12 to 0 hr pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | — |
| T1/2: Apparent Terminal Half-life | -12 to 0 pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | — |
| Baseline Corrected Cmax: Baseline Corrected Maximum Serum Concentration | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). Negative concentrations were set to zero. |
| Baseline Corrected AUC (0-t): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Serum Concentration) | -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose | Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). Negative concentrations were set to zero. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety Assessment: Adverse Events | Up to 10 days after first study drug administration at Day 1 of Period 1 | Number of participants with adverse events after study drug administration |
| Safety Assessment (Vital Signs) | Up to 10 days after first study drug administration at Day 1 of Period 1 | Number of participants with clinically significant findings in vital signs by investigator after study drug administration. |
Countries
United States
Participant flow
Recruitment details
Subjects took part in the study at one investigative site in the United States from 15 March 2016 to 10 April 2016.
Participants by arm
| Arm | Count |
|---|---|
| Group 1, Inosine With Food Then Without Food Group 1 subjects will take inosine with food on day 1 after an overnight fast and will take a second dose of inosine without food on day 8 after an overnight fast.
Inosine: Inosine, 1000 mg | 9 |
| Group 2, Inosine Without Food Then With Food Group 2 subjects will take inosine without food on day 1 after an overnight fast and will take a second dose of inosine with food on day 8 after an overnight fast.
Inosine: Inosine, 1000 mg | 9 |
| Total | 18 |
Baseline characteristics
| Characteristic | Group 2, Inosine Without Food Then With Food | Group 1, Inosine With Food Then Without Food | Total |
|---|---|---|---|
| Age, Continuous | 34.67 years STANDARD_DEVIATION 5.92 | 41.44 years STANDARD_DEVIATION 16.37 | 38.06 years STANDARD_DEVIATION 12.44 |
| Race/Ethnicity, Customized Black or African American | 4 participants | 4 participants | 8 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 4 participants | 5 participants | 9 participants |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 18 | 0 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
AUC (0-inf): Area Under the Serum Concentration-time Curve From Time 0 to Infinity
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
Population: AUC (0-inf) of 1 subject was not able to be calculated based on the serum concentration-time curve of the subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | AUC (0-inf): Area Under the Serum Concentration-time Curve From Time 0 to Infinity | 2040 mg*hr/dL | Standard Deviation 2261 |
| Inosine Fasted | AUC (0-inf): Area Under the Serum Concentration-time Curve From Time 0 to Infinity | 2031 mg*hr/dL | Standard Deviation 2278 |
Primary
AUC (0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Plasma Concentration)
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | AUC (0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Plasma Concentration) | 267 mg*hr/dL | Standard Deviation 30.2 |
| Inosine Fasted | AUC (0-t): Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Plasma Concentration) | 268 mg*hr/dL | Standard Deviation 26.4 |
Comparison: To assess the effect of food on the PK of urate, analyses of variance (ANOVA) using a linear mixed-effects model was fitted to the natural logarithmic transformation of PK parameters of urate. The linear mixed-effects model will include subject as a random effect, and treatment, period, and sequence as fixed effects. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters between fed and fasted treatments, based on log-transformed data.90% CI: [96.9, 102]
Primary
Baseline Corrected AUC (0-inf): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Infinity
Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2).
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose
Population: Baseline Corrected AUC (0-inf) values of 2 subjects were not able to be calculated based on the serum concentration-time curve of these subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | Baseline Corrected AUC (0-inf): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Infinity | 80.4 mg*hr/dL | Standard Deviation 84.2 |
| Inosine Fasted | Baseline Corrected AUC (0-inf): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Infinity | 83.0 mg*hr/dL | Standard Deviation 86.3 |
Primary
Baseline Corrected AUC (0-t): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Serum Concentration)
Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). Negative concentrations were set to zero.
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | Baseline Corrected AUC (0-t): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Serum Concentration) | 36.1 mg*hr/dL | Standard Deviation 15.1 |
| Inosine Fasted | Baseline Corrected AUC (0-t): Baseline Corrected Area Under the Serum Concentration-time Curve From Time 0 to Time t (Time of Last Quantifiable Serum Concentration) | 39.3 mg*hr/dL | Standard Deviation 13.3 |
Comparison: To assess the effect of food on the PK of urate, analyses of variance (ANOVA) using a linear mixed-effects model was fitted to the natural logarithmic transformation of PK parameters of urate. The linear mixed-effects model will include subject as a random effect, and treatment, period, and sequence as fixed effects. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters between fed and fasted treatments, based on log-transformed data.90% CI: [62.1, 112]
Primary
Baseline Corrected Cmax: Baseline Corrected Maximum Serum Concentration
Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2). Negative concentrations were set to zero.
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | Baseline Corrected Cmax: Baseline Corrected Maximum Serum Concentration | 1.73 mg/dL | Standard Deviation 0.46 |
| Inosine Fasted | Baseline Corrected Cmax: Baseline Corrected Maximum Serum Concentration | 1.65 mg/dL | Standard Deviation 0.37 |
Comparison: To assess the effect of food on the PK of urate, analyses of variance (ANOVA) using a linear mixed-effects model was fitted to the natural logarithmic transformation of PK parameters of urate. The linear mixed-effects model will include subject as a random effect, and treatment, period, and sequence as fixed effects. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters between fed and fasted treatments, based on log-transformed data.90% CI: [90.9, 118]
Primary
Baseline Corrected T1/2: Baseline Corrected Apparent Terminal Half-life
Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2).
Time frame: -12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
Population: Baseline Corrected T 1/2 values for 2 subjects were not able to be calculated based on the serum concentration-time curve of these subjects.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | Baseline Corrected T1/2: Baseline Corrected Apparent Terminal Half-life | 44.3 hr | Standard Deviation 71.5 |
| Inosine Fasted | Baseline Corrected T1/2: Baseline Corrected Apparent Terminal Half-life | 44.7 hr | Standard Deviation 76.2 |
Primary
Baseline Corrected Tmax: Baseline Corrected Time of Maximum Serum Concentration
Correction for individual endogenous urate levels was done by subtracting the individual mean endogenous baseline concentration prior to dosing from each post-dose concentration in the profile. The two samples collected at -12 h and 0 h (pre-dose) before the meal were used to measure the mean endogenous baseline concentrations in each dosing period (periods 1 and 2).
Time frame: -12 to 0 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inosine Fed | Baseline Corrected Tmax: Baseline Corrected Time of Maximum Serum Concentration | 3.0 hr |
| Inosine Fasted | Baseline Corrected Tmax: Baseline Corrected Time of Maximum Serum Concentration | 3.0 hr |
Primary
Cmax: Maximum Observed Serum Urate Concentration
Time frame: -12 to 0 hrs pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36 and 48 hrs post-dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | Cmax: Maximum Observed Serum Urate Concentration | 6.6 mg/dL | Standard Deviation 0.7 |
| Inosine Fasted | Cmax: Maximum Observed Serum Urate Concentration | 6.4 mg/dL | Standard Deviation 0.6 |
Comparison: To assess the effect of food on the PK of urate, analyses of variance (ANOVA) using a linear mixed-effects model was fitted to the natural logarithmic transformation of PK parameters of urate. The linear mixed-effects model will include subject as a random effect, and treatment, period, and sequence as fixed effects. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters between fed and fasted treatments, based on log-transformed data.90% CI: [98, 108]
Primary
T1/2: Apparent Terminal Half-life
Time frame: -12 to 0 pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
Population: T 1/2 of 1 subject was not able to be calculated based on the serum concentration-time curve of the subject.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inosine Fed | T1/2: Apparent Terminal Half-life | 242 hr | Standard Deviation 341 |
| Inosine Fasted | T1/2: Apparent Terminal Half-life | 241 hr | Standard Deviation 331 |
Primary
Tmax: Time of Maximum Serum Concentration
Time frame: -12 to 0 hr pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Inosine Fed | Tmax: Time of Maximum Serum Concentration | 3.0 hr |
| Inosine Fasted | Tmax: Time of Maximum Serum Concentration | 3.0 hr |
Secondary
Safety Assessment: Adverse Events
Number of participants with adverse events after study drug administration
Time frame: Up to 10 days after first study drug administration at Day 1 of Period 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inosine Fed | Safety Assessment: Adverse Events | 0 participants |
| Inosine Fasted | Safety Assessment: Adverse Events | 0 participants |
Secondary
Safety Assessment (Vital Signs)
Number of participants with clinically significant findings in vital signs by investigator after study drug administration.
Time frame: Up to 10 days after first study drug administration at Day 1 of Period 1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inosine Fed | Safety Assessment (Vital Signs) | 0 participants |
| Inosine Fasted | Safety Assessment (Vital Signs) | 0 participants |