Safety and Pharmacokinetics of an Extract of Naringenin (Citrus)

Clinical Safety and Pharmacokinetic Evaluation of Naringenin: Single Dose Escalation Randomized Double Blind Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Safety Issues
• Intervention / Treatment: Dietary supplement: Naringenin; Other: Placebo

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.

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

Contacts and Locations

Study Locations

• United States
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Pennington Biomedical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 150 mg dose; Blood will be drawn at at 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours to measure serum naringenin concentrations in response to a single 150 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin.	Dietary supplement: Naringenin; An extract of Citrus Sinensis containing naringenin and its precursor naringin
Experimental: 300 mg dose; Blood will be drawn at at 0, and 4 hours to measure serum naringenin concentrations in response to a single 300 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin.	Dietary supplement: Naringenin; An extract of Citrus Sinensis containing naringenin and its precursor naringin
Experimental: 600 mg dose; Blood will be drawn at at 0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours to measure serum naringenin concentrations in response to a single 600 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin.	Dietary supplement: Naringenin; An extract of Citrus Sinensis containing naringenin and its precursor naringin
Experimental: 900 mg dose; Blood will be drawn at at 0, and 4 hours to measure serum naringenin concentrations in response to a single 900 mg oral dose of an extract of Citrus sinensis (sweet orange) containing naringenin and its precursor naringin.	Dietary supplement: Naringenin; An extract of Citrus Sinensis containing naringenin and its precursor naringin
Placebo Comparator: Placebo; Subjects in the first cohort will receive 150 mg and 300 mg ascending doses of naringenin and subjects in the second cohort will receive 600 mg and 900 mg ascending doses of naringenin. Each cohort will also have a placebo group.	Other: Placebo; Cellulose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Adverse events were collected over approximately five weeks which included three study days and two washout periods of at least one week.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
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.	0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
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.	24 hours
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.	0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
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.	0, 2, 3, 3.5, 4, 4.5, 6, 8,12, and 24 hours
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.	0 and 4 hours

Collaborators and Investigators

• Sponsor: Pennington Biomedical Research Center
• Collaborators: Louisiana Clinical and Translational Science Center
• Investigators: Principal Investigator: Candida Rebello, Pennington Biomedical Research Center

Publications and helpful links

General Publications

• Mulvihill EE, Burke AC, Huff MW. Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis. Annu Rev Nutr. 2016 Jul 17;36:275-99. doi: 10.1146/annurev-nutr-071715-050718. Epub 2016 May 4.

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2018
• Primary Completion (Actual): September 28, 2018
• Study Completion (Actual): September 28, 2018

Study Registration Dates

• First Submitted: June 22, 2018
• First Submitted That Met QC Criteria: July 9, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 2, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Gastrointestinal Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Antagonists; Anti-Ulcer Agents; Naringenin
• Other Study ID Numbers: 2018-011

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No