A Food-Drug Interaction Study of Serum Urate After Oral Inosine

A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to Evaluate the Effects of Food on the Pharmacokinetics of Urate After a Single Dose of Inosine in Healthy Male Subjects

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Evansville, Indiana, United States, 47710
      • Covance Clinical Research Unit Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1, Inosine with 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.	Drug: Inosine; Inosine, 1000 mg
EXPERIMENTAL: Group 2, Inosine without 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.	Drug: Inosine; Inosine, 1000 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	-12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
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.	-12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose
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).	-12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose
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).	-12 to 0 h pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hrs post-dose
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).	-12 to 0 hr pre-dose and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48 hrs post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Assessment (Vital Signs)	Number of participants with clinically significant findings in vital signs by investigator after study drug administration.	Up to 10 days after first study drug administration at Day 1 of Period 1
Safety Assessment: Adverse Events	Number of participants with adverse events after study drug administration	Up to 10 days after first study drug administration at Day 1 of Period 1

Collaborators and Investigators

• Sponsor: Michael Alan Schwarzschild
• Collaborators: Michael J. Fox Foundation for Parkinson's Research; The Parkinson Alliance

Publications and helpful links

General Publications

• Anton FM, Garcia Puig J, Ramos T, Gonzalez P, Ordas J. Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate. Metabolism. 1986 Apr;35(4):343-8. doi: 10.1016/0026-0495(86)90152-6.
• Cuhadar S, Koseoglu M, Atay A, Dirican A. The effect of storage time and freeze-thaw cycles on the stability of serum samples. Biochem Med (Zagreb). 2013;23(1):70-7. doi: 10.11613/bm.2013.009.
• Dirar AM, A.D., Abdelsalam KEA. Effect of Storage Time and Temperature on some Serum Analytes. International Journal of Pathology 8: 68-71, 2010.
• Parkinson Study Group SURE-PD Investigators; Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528.
• Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler. 2001 Oct;7(5):313-9. doi: 10.1177/135245850100700507.
• Yamamoto T, Moriwaki Y, Cheng J, Takahashi S, Tsutsumi Z, Ka T, Hada T. Effect of inosine on the plasma concentration of uridine and purine bases. Metabolism. 2002 Apr;51(4):438-42. doi: 10.1053/meta.2002.31322.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (ACTUAL): April 1, 2016
• Study Completion (ACTUAL): May 1, 2016

Study Registration Dates

• First Submitted: November 23, 2015
• First Submitted That Met QC Criteria: November 24, 2015
• First Posted (ESTIMATE): November 25, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 29, 2017
• Last Update Submitted That Met QC Criteria: February 27, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Other Study ID Numbers: INO-PD-P3-2015-FE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO