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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: isoquercetin or quercetin


Participation Criteria
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Eligibility Criteria
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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: Estimated GFR >35 (formula), Platelet count >65 K/uL, Hemoglobin >10.5 grams/dL 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quercetin<br>Single dose of quercetin with or without ascorbic acid | Drug: isoquercetin or quercetin<br>* Single dose PK/PD study<br>|
| Active Comparator: Isoquercetin<br>Single dose of isoquercetin with or without ascorbic acid | Drug: isoquercetin or quercetin<br>* Single dose PK/PD study<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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quercetin, isoquercetin, pharmacokinetic, pharmacodynamic