Type of Study: Single Ascending Doses (SAD) Study Objectives: To characterize the pharmacokinetic (PK) profile of JOTROL (resveratrol) following oral administration of SAD ranging from 200 mg up to a dose currently estimated at 1,000 mg, in healthy subjects. To evaluate the safety and tolerability of JOTROL To evaluate the effect of food on the PK profile of JOTROL. Study Design: Phase I, randomized, open-label, sequential SAD study with a food effect evaluation. Blood plasma and urine samples will be assessed for resveratrol and key metabolite content. Type of Control: No control Test Product: JOTROL (resveratrol) 100 mg resveratrol in 1000 mg softgel capsule for oral administration Dosage Regimen: Planned dose levels of resveratrol: 200 mg, 500 mg, and 1,000 mg. Following completion of each dose level, PK, safety, and tolerability data will be evaluated; dose levels may be adjusted. Route of Administration: Oral gelcaps with water Number of Subjects: 24 subjects will be included in Part 1; only 16 subjects, who completed Part 1, will be included in Part 2. Subjects: Healthy, non-smoker, adult males or females, ≥ 18 and ≤ 75 years of age Study Duration: Participation of each subject in this study should last approximately 1 to 1.5 months (for subjects participating in study Part 1 only) and 1.5 to 2 months (for subjects participating in both study parts).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
24
Low (first) dose of single ascending dose study
Second (intermediate) dose of single ascending dose study
Third (highest) dose of single ascending dose study
500 mg resveratrol as JOTROL administered to assess influence of food
inVentiv Health Clinical Research Services LLC, a Syneos Health company (" Syneos Health ")
Miami, Florida, United States
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was defined as any untoward medical occurrence (including clinically significant \[CS\] vital signs measurements or laboratory results) or worsening of a pre-existing condition in a participant administered a pharmaceutical product during the course of the study, whether related or not to the study medication. TEAEs were defined as AE that occurred on or after the date and time of study drug administration or those that first occurred pre-dose but worsened by increase in occurrence or severity after study drug administration. TEAEs includes both serious and non-serious TEAEs.
Time frame: From first dose of study drug administration up to 131 days
Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity (AUC0-inf) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported. AUC(0-infinity) of resveratrol, resveratrol-3-glucuronide, resveratrol-4'-glucuronide, and resveratrol-3-sulfate in plasma were reported and calculated as AUC0-t + Ct/Kel, where Ct is the last observed measurable concentration, AUC0-t is Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration and Kel is Elimination rate constant.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
AUC0-t was Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration. AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Maximum Observed Plasma Concentration (Cmax) for Resveratrol and Its Metabolites (Resveratrol-3-glucuronide, Resveratrol-4'-Glucuronide, and Resveratrol-3-sulfate)
Cmax was the maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Residual Area for Resveratrol
Residual area for resveratrol in plasma was calculated and reported. The residual area was calculated as 100\*(1- AUC0-t / AUC0-inf) where AUC0-t (h\*ng/mL) = area under the concentration-time curve from time zero to the last measurable concentration and AUC0-inf (h\*ng/mL) = area under the plasma concentration-time curve from time 0 to time of infinity.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Time to Maximum Observed Plasma Concentration (Tmax) for Resveratrol
Tmax was time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Elimination Half-Life (T1/2 el) for Resveratrol
Elimination half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Elimination Rate Constant (Kel) for Resveratrol
Kel was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose and 0.133, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Cumulative Urinary Excretion From Time Zero to Time t (Ae0-t) for Resveratrol
Cumulative urinary excretion from time zero to time t, calculated as the sum of the amounts excreted over each collection interval. The amount excreted in urine for each time interval was calculated as the urine concentration multiplied by the urine volume.
Time frame: Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1
Maximum Rate of Urinary Excretion (Rmax) for Resveratrol
Maximum rate of urinary excretion, calculated by dividing the amount of drug excreted in each collection interval by the time over which it was collected.
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Time frame: Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1
Time of Rmax (Tmax) for Resveratrol
Tmax was the time after administration of a drug when the Rmax is reached.
Time frame: Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1
Renal Clearance (CLr) for Resveratrol
CLr was calculated as Ae0-t/AUC0-t (plasma) where t is Tlast.
Time frame: Pre-dose and 4, 8, 12, 24, and 32 hours post-dose on Day 1