Pharmacokinetics, Safety Issues
Conditions
Brief summary
This study evaluates the safety of administering single ascending doses (150, 300, 600, and 900 mg) of a citrus extract of the flavonoid narigenin, and assesses the blood concentrations of naringenin following oral administration of the extract.
Detailed description
Naringenin is a component of food with therapeutic potential to improve glucose metabolism. In order to explore the mechanisms by which naringenin may increase energy expenditure and improve glucose metabolism in humans, it is of vital importance that the safety, tolerability, and bioavailability of naringenin are evaluated, when administered to humans. This study tests the safety of four doses of a citrus extract of naringenin and measures serum concentrations of naringenin at the 150 mg and 600 mg doses over a period of 24 hours, and at the 300 and 900 mg doses at four hours after subjects have been given the respective doses of naringenin.
Interventions
DIETARY_SUPPLEMENTNaringenin
An extract of Citrus Sinensis containing naringenin and its precursor naringin
OTHERPlacebo
Cellulose
Sponsors
Louisiana Clinical and Translational Science Center
Pennington Biomedical Research Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Except for the pharmacist who will prepare and dispense the capsules, all study staff and the investigators will be blinded to the randomization.
Intervention model description
The study consists of two cohorts of nine subjects each. In the first cohort subjects will receive the 150 mg dose and proceed to the 300 mg dose only if the 150 mg dose is deemed safe. The study is a double blind randomized controlled crossover trial, therefore, subjects could receive a placebo at the first or second visit. Similarly in the second cohort, 600 mg and 900 mg doses will be evaluated.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Adult (≥18 years) * Body mass index between 20 and 35 kg/m2 * Must have fasting blood sugar \<126 mg/dL) * Must be willing to refrain from consuming citrus fruits and tomato in any form, for 36 hours prior to each test day.
Exclusion criteria
* Report citrus allergies. * Report a history of cardiovascular disease, diabetes, or cancer * Have evidence of hepatic disease or dysfunction * Are currently pregnant or breastfeeding * Are women of childbearing potential who will not use an effective method of birth control * Chronically use of medications except over the counter medications that have been stopped 72 hours prior to the study visit * Report clinically significant GI malabsorption syndromes * Have clinically significant abnormal laboratory markers * Anticipate surgery during the study period. * Report history of substance abuse or alcoholism or significant psychiatric disorder that would interfere with the ability to complete the study. * Have donated blood during the month prior to study entry or plan to do so during the study. * Have participated in other studies using an investigational drug during the preceding three months. * Are current smokers or have smoked within the previous three months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week. | All adverse events will be recorded following the first administration of the study product or placebo. The study physician in consultation with the coordinator will review and determine whether a subject can be administered the next ascending dose. The cohorts will be run in series. There will be an interval of up to four weeks between the two cohorts. During this time an interim analysis will be conducted and a safety summary of adverse events for Cohort 1 will be compiled and reviewed by the investigators. Dose safety will be investigated by compiling by treatment (e.g. 150 mg dose, 300 mg dose, placebo) a list of adverse events. The frequency of these events will be counted and compared with the placebo group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The maximal serum concentration will be determined. |
| Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses | 24 hours | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The time to peak serum naringenin concentration will be determined. |
| Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The area under the serum concentration versus time curve will be determined. |
| Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The apparent oral clearance of naringenin will be determined. |
| Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses | 0 and 4 hours | Blood will be drawn at 0 hours and 4 hours following ingestion of the 300 and 900mg doses of naringenin and serum naringenin concentrations will be measured. |
| Measurement of Half Life of Naringenin at 150 and 600 mg Doses | 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours | Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The half life of naringenin will be determined. |
Countries
United States
Participant flow
Recruitment details
38 subjects were screened for eligibility between May 25, 2018 and September 12, 2018.
Pre-assignment details
Of the 38 participants screened, 10 participants did not meet the study criteria, 7 had schedule conflicts and declined to participate, and 3 were screened before the study was determined to have met the recruiting goal. 18 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: NAR150, Placebo, NAR300 Cohort 1 Sequence 1: NAR150 first, then Placebo, then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Cohort 1: NAR150, NAR300, Placebo Cohort 1 Sequence 2: NAR150 first, then NAR300 and then Placebo. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Cohort 1: Placebo, NAR150, NAR300 Cohort 1 Sequence 3: Placebo first, then NAR150, and then NAR300. 150 and 300 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 300 mg (NAR300) naringenin doses were provided in two capsules. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Cohort 2. NAR600, Placebo, NAR900 Cohort 2 Sequence 1: NAR600, then Placebo, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Cohort 2: NAR600, NAR900, Placebo Cohort 2 Sequence 2: NAR600, then NAR900, and then Placebo. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Cohort 2: Placebo, NAR600, NAR900 Cohort 2 Sequence 3: Placebo, NAR600, and then NAR300. 600 and 900 mg doses of naringenin where each 150 mg dose capsule (NAR150) contained 536 mg of the extract (28% naringenin determined in quantitative analysis). The 600 mg (NAR600) and 900 mg (NAR900) doses of naringenin were provided in four and six 150 mg capsules respectively. The placebo capsules contained microcystalline cellulose and were similar in appearance. | 3 |
| Total | 18 |
Baseline characteristics
| Characteristic | Cohort 1: NAR150, Placebo, NAR300 | Total | Cohort 2: Placebo, NAR600, NAR900 | Cohort 2: NAR600, NAR900, Placebo | Cohort 2. NAR600, Placebo, NAR900 | Cohort 1: Placebo, NAR150, NAR300 | Cohort 1: NAR150, NAR300, Placebo |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.33 Years STANDARD_DEVIATION 16.36 | 38.0 Years STANDARD_DEVIATION 15.1 | 55.33 Years STANDARD_DEVIATION 31.94 | 30.67 Years STANDARD_DEVIATION 17.7 | 37.0 Years STANDARD_DEVIATION 21.36 | 33 Years STANDARD_DEVIATION 19.05 | 48.0 Years STANDARD_DEVIATION 27.71 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 12 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants |
| Serum Naringenin Concentrations | 0.02 uM STANDARD_DEVIATION 0.01 | 0.008 uM STANDARD_DEVIATION 0.004 | 0 uM STANDARD_DEVIATION 0 | 0 uM STANDARD_DEVIATION 0 | 0 uM STANDARD_DEVIATION 0 | 0 uM STANDARD_DEVIATION 0 | 0.01 uM STANDARD_DEVIATION 0 |
| Sex: Female, Male Female | 2 Participants | 12 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 6 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 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 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 18 |
| other Total, other adverse events | 3 / 9 | 3 / 9 | 2 / 9 | 1 / 9 | 4 / 18 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 18 |
Outcome results
Primary
Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin
All adverse events will be recorded following the first administration of the study product or placebo. The study physician in consultation with the coordinator will review and determine whether a subject can be administered the next ascending dose. The cohorts will be run in series. There will be an interval of up to four weeks between the two cohorts. During this time an interim analysis will be conducted and a safety summary of adverse events for Cohort 1 will be compiled and reviewed by the investigators. Dose safety will be investigated by compiling by treatment (e.g. 150 mg dose, 300 mg dose, placebo) a list of adverse events. The frequency of these events will be counted and compared with the placebo group.
Time frame: Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week.
Population: Subjects who completed the study
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Skin and Subcutaneous Tissue Disorders | 1 Participants |
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Gastrointestinal | 1 Participants |
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Musculoskeletal | 1 Participants |
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Nervous System Disorders | 1 Participants |
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Respiratory | 0 Participants |
| 150 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Eye Disorders | 0 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Respiratory | 0 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Eye Disorders | 0 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Skin and Subcutaneous Tissue Disorders | 2 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Musculoskeletal | 2 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Nervous System Disorders | 0 Participants |
| 300 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Gastrointestinal | 0 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Nervous System Disorders | 0 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Respiratory | 1 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Skin and Subcutaneous Tissue Disorders | 0 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Musculoskeletal | 0 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Gastrointestinal | 0 Participants |
| 600 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Eye Disorders | 1 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Nervous System Disorders | 0 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Gastrointestinal | 0 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Musculoskeletal | 0 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Eye Disorders | 0 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Respiratory | 0 Participants |
| 900 mg Dose | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Skin and Subcutaneous Tissue Disorders | 1 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Respiratory | 0 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Musculoskeletal | 1 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Gastrointestinal | 2 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Eye Disorders | 0 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Nervous System Disorders | 0 Participants |
| Placebo | Incidence of Treatment-emergent Adverse Events Following a Single Dose of a Citrus Extract of Naringenin | Skin and Subcutaneous Tissue Disorders | 1 Participants |
Secondary
Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses
Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The apparent oral clearance of naringenin will be determined.
Time frame: 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
Population: Subjects who completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Dose | Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses | 10.21 L/hour | Standard Error 2.34 |
| 300 mg Dose | Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses | 13.7 L/hour | Standard Error 2.34 |
| 600 mg Dose | Measurement of Apparent Oral Clearance of Naringenin at 150 and 600 mg Doses | 0 L/hour | Standard Error 0 |
Secondary
Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses
Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The area under the serum concentration versus time curve will be determined.
Time frame: 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
Population: Subjects who completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Dose | Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses | 18.41 (ug/mL) x hour | Standard Error 6.61 |
| 300 mg Dose | Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses | 54.19 (ug/mL) x hour | Standard Error 6.61 |
| 600 mg Dose | Measurement of Area Under the Serum Naringenin Concentration Versus Time Curve at 150 and 600 mg Doses | 0.08 (ug/mL) x hour | Standard Error 6.61 |
Secondary
Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses
Blood will be drawn at 0 hours and 4 hours following ingestion of the 300 and 900mg doses of naringenin and serum naringenin concentrations will be measured.
Time frame: 0 and 4 hours
Population: Subjects who participated in the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Dose | Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses | 10.7 uM | Standard Error 5.64 |
| 300 mg Dose | Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses | 43.1 uM | Standard Error 5.3 |
| 600 mg Dose | Measurement of Four-hour Concentration of Serum Naringenin at 300 and 900 mg Doses | 0.3 uM | Standard Error 4.2 |
Secondary
Measurement of Half Life of Naringenin at 150 and 600 mg Doses
Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The half life of naringenin will be determined.
Time frame: 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
Population: Subjects who completed the study. The half-life uses all the pooled data to calculate an estimate of the slope (k) to determine the half-life estimate. We did not calculate the slope of each individual subject.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 150 mg Dose | Measurement of Half Life of Naringenin at 150 and 600 mg Doses | 3.0 hour |
| 300 mg Dose | Measurement of Half Life of Naringenin at 150 and 600 mg Doses | 2.65 hour |
| 600 mg Dose | Measurement of Half Life of Naringenin at 150 and 600 mg Doses | 0 hour |
Secondary
Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses
Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum concentrations will be measured. The maximal serum concentration will be determined.
Time frame: 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Dose | Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses | 4.29 ug/mL | Standard Error 2.15 |
| 300 mg Dose | Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses | 13.19 ug/mL | Standard Error 2.15 |
| 600 mg Dose | Measurement of Maximal Concentration of Serum Naringenin at 150 and 600 mg Doses | 0.009 ug/mL | Standard Error 2.15 |
Secondary
Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses
Blood will be drawn over a period of 24 hours following ingestion of the 150 and 600mg doses of naringenin and serum naringenin concentrations will be measured. The time to peak serum naringenin concentration will be determined.
Time frame: 24 hours
Population: Subjects who completed the study
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 150 mg Dose | Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses | 3.17 hour | Standard Error 0.74 |
| 300 mg Dose | Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses | 2.41 hour | Standard Error 0.74 |
| 600 mg Dose | Measurement of Time to Peak Concentration of Serum Naringenin at 150 and 600 mg Doses | 0 hour | Standard Error 0 |