Quercetin PK/PD Study in Healthy Adults and Patients With Hypercoagulable States (PK/PD)

Pharmacokinetic and Pharmacodynamic Study of Oral Quercetin and Isoquercetin in Healthy Adults and Patients With Hypercoagulable States.

The goal of this study is to evaluate how much quercetin or isoquercetin is absorbed after a single dose and evaluate for pharmacokinetic inhibition of protein disulfide isomerase. Pharmacodynamic studies will also be performed in an additional cohort of 10 patients with evidence of antiphospholipid antibodies

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: isoquercetin or quercetin

Detailed Description

To compare the absorption and activity of quercetin or isoquercetin with or without ascorbic acid in healthy adults. Oral chews containing quercetin (500mg) or isoquercetin(500 mg total) with or without ascorbic acid will be given. Pharmacokinetic parameters (AUC, Cmax, Tmax, elimination half-life) will be determined over 24 hours (8 time points). Pharmacodynamic inhibition of protein disulfide isomerase activity will also be assessed.

In addition to healthy subjects, a cohort of 10 individuals with antiphospholipid antibodies will participate. These participants will receive isoquercetin 1000 mg and have pharmacodynamics studies performed at time 0 and 4 hours.

All study drugs will be provided by Quercegen Pharma.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Subject is willing to participate and provide informed consent
• Subject is considered reliable and capable of adhering to the protocol per the judgment of the Investigator

• Subjects in group D must exhibit good organ reserves (within prior 4 weeks) defined as:

  1. Estimated GFR >35 (formula),
  2. Platelet count >65 K/uL,
  3. Hemoglobin >10.5 grams/dL
  4. Total bilirubin <2.0 mg/dL
• Minimum age 18 years old
• Body mass index (BMI) between 18 and 35 kg/m2
• For cohort D (antiphospholipid antibodies) a. Subjects in group D must have at least one positive antiphospholipid antibody within the last 8 weeks and/or previous confirmed antibodies (2 or more occasions at least 12 weeks apart) : i. Positive lupus anticoagulant ii. anticardiolipin antibody IgM or IgG (>40U GPL) iii. anti-β2 Glycoprotein1 antibody titer (>35 units)

Exclusion Criteria

• Pregnant. If female of child-bearing age, negative urinary pregnancy test prior to dosing of quercetin or isoquercetin
• No history of malabsorptive gastrointestinal disorder

• Currently taking aspirin, NSAIDS, warfarin, low-molecular weight heparin or other anticoagulants (such as direct thrombin inhibitors or factor X inhibitors)

  a. Note: Study subjects taking aspirin or NSAIDS, if treating physician concurs, are permitted to enroll if plan to hold for aspirin 10 days or NSAIDS 24 hours prior to dosing of quercetin/isoquercetin

• Prescribed niacin for hyperlipidemia
• Known HIV
• History of sensitivity or intolerance to flavonoids, niacin or ascorbic acid
• May not have uncontrolled intercurrent illness including, but not limited to ongoing or active infection, hepatitis, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Quercetin; Single dose of quercetin with or without ascorbic acid	Drug: isoquercetin or quercetin; Single dose PK/PD study
Active Comparator: Isoquercetin; Single dose of isoquercetin with or without ascorbic acid	Drug: isoquercetin or quercetin; Single dose PK/PD study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC	AUC 0-24 hours of measured plasma quercetin aglycone for Arms A1, B1, A2, B2, C Collected at timepoints: baseline and 1, 2, 4, 6, 8, and 24 hours after dose. PK and PDI samples were not measured for Arm D (anti-phospholipid antibody cohort)	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reductase Activity of PDI Using Dieosin Glutathione Disulfide	Measurement of protein disulfide inhibition in plasma using a fluorescent PDI substrate (dieosin glutathione disulfide)	2 hours. Not measured in D
Platelet-induced Thrombin Generation (U/mL)	Thrombin induced thrombin generation measured in patient plasma	4 hours

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Jeffrey Zwicker, MD, Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Stopa JD, Neuberg D, Puligandla M, Furie B, Flaumenhaft R, Zwicker JI. Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation. JCI Insight. 2017 Jan 12;2(1):e89373. doi: 10.1172/jci.insight.89373.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: May 10, 2012
• First Submitted That Met QC Criteria: November 5, 2012
• First Posted (Estimate): November 7, 2012

Study Record Updates

• Last Update Posted (Actual): October 12, 2020
• Last Update Submitted That Met QC Criteria: October 9, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: pharmacokinetic; quercetin; pharmacodynamic; isoquercetin
• Additional Relevant MeSH Terms: Hematologic Diseases; Thrombophilia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Antioxidants; Quercetin
• Other Study ID Numbers: 2012P000022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Contact PI
• IPD Sharing Time Frame: 3 years
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No