Clinical Evaluation of the Pharmacokinetic Goldenseal-Metformin Interaction in Diabetic Patients

Study Overview
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Brief Summary
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Supplements containing goldenseal, a perennial herb native to North America, have consistently ranked among the top 20 highest selling natural products throughout the last decade. Goldenseal products are marketed as licensed natural health products in Canada and as dietary supplements in the United States. Natural products made from dried roots of the goldenseal plant are purported to have therapeutic value and are used to self-treat a range of medical complications, including the common cold, allergic rhinitis, and digestive disorders, such as diarrhea and constipation. Based on a previous clinical study, goldenseal have been shown to precipitate pharmacokinetic interactions with metformin in healthy volunteers. This follow-up study aims to evaluate the goldenseal-metformin interaction in type 2 diabetic patients. Results from this proposed clinical study will (1) characterize the pharmacokinetic interaction between the botanical dietary supplement goldenseal and anti-diabetic drug metformin, (2) provide evidence-based recommendations to mitigate drug interaction risks, and (3) contribute to the development of a comprehensive strategy for effectively assessing other potential natural-product drug interactions.

Detailed Description
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Many patient groups, including those afflicted with cardiovascular disease, cancer, HIV/AIDS, hepatitis C, and diabetes, often supplement their prescribed pharmacotherapeutic regimens with herbal and other natural products, raising concern for adverse interactions. Unlike for drug-drug interactions, rigorous, harmonized guidelines for assessing the risk of natural product-drug interactions do not exist. The NCCIH-funded Center of Excellence for Natural Product Drug Interaction (NaPDI) Research was established in September 2015. The mission of the NaPDI Center is to provide leadership in the identification, evaluation, and dissemination of potential clinically meaningful pharmacokinetic natural product-drug interactions. Goldenseal is one of four high priority natural products selected by the NaPDI Center for further evaluation for drug interaction potential. A recent clinical study completed by researchers at the NaPDI center showed that a well-characterized, adulterant- and contaminant-free goldenseal product administered to 16 healthy volunteers (3 g daily by mouth for 6 consecutive days) resulted in a significant decrease (23%) in metformin systemic exposure [area under the plasma concentration-time curve (AUC)] with no change in half-life or renal clearance. Based on these clinical observations, along with complementary in vitro data, the current working hypothesis is that goldenseal interacts with intestinal organic cation transporter 1 to alter metformin disposition. These observations may have clinical implications for diabetic patients, as metformin is the first-line treatment and most prescribed anti-diabetic medication for type 2 diabetes. The objective of this study is to assess the potential for goldenseal to alter the pharmacokinetics and clinical effects of standard metformin treatment in well-controlled adult type 2 diabetic patients. Transporter inhibition represents an understudied mechanism of natural product-drug interactions. The proposed clinical study will be the first of its kind to evaluate whether such pharmacokinetic interactions can potentially affect clinical outcomes. The knowledge gained from these efforts will ultimately build upon a systematic framework for effectively studying other transporter-mediated natural product-drug interactions.

Official Title
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Clinical Evaluation of the Pharmacokinetic Goldenseal-Metformin Interaction in Diabetic Patients

Conditions
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Interaction, Adverse Herb-Drug, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Midazolam Hcl 1Mg/Ml Inj
* Dietary Supplement: Goldenseal (Hydrastis canadensis)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: are 18-65 years old and healthy have been medically diagnosed with Type 2 diabetes and currently taking metformin (1- 2 g daily), but otherwise healthy as determined by the study physician have an HbA1c < 8% as determined by laboratory analysis on initial screening are not taking any medications, dietary/herbal supplements, or citrus juices that can interfere with your ability to eliminate the study drugs and goldenseal from your body are willing to stop consuming alcohol, caffeinated beverages or other caffeine- containing products the evening before and the morning of the first day of each study arm are female and are willing to use an acceptable method of birth control that does not include oral birth control pills or patches (such as abstinence, copper IUD, condom) can provide written informed consent (and assent when applicable) obtained from subject or subject's legal representative and ability for the subject to comply with the requirements of the study Exclusion Criteria: have an HbA1c ≥ 8% have other chronic illnesses other than type 2 diabetes (e.g., type 1 diabetes, kidney disease, hepatic disease, uncontrolled hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS) have a hematologic (blood) disorder have a history of drug or alcohol abuse have any major psychiatric illness are pregnant or breastfeeding have a history of intolerance or allergy to midazolam or goldenseal products are taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products) known to alter the pharmacokinetics of either study drug or goldenseal constituents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm 1: Baseline<br>Twenty type 2 diabetic subjects (10 men, 10 women) will be administered a single dose of midazolam (0.5 mg) intravenously via a peripherally inserted catheter in conjunction with their daily oral administration of metformin. Plasma and urine will be collected from 0-24 hours post-midazolam administration. Participants will take their metformin as prescribed for the entirety of the study with no interruption in pharmacotherapy. | Drug: Midazolam Hcl 1Mg/Ml Inj<br>* 0.5 mL of an intravenous solution (1 mg/mL) will be administered.<br>* Other names: Versed;|
| Experimental: Study Arm 2: Acute Goldenseal Exposure<br>For Arm 2, the same 20 subjects will be administered a single dose of goldenseal (3.3 g) orally 30 minutes prior to administration of midazolam (as described in Arm 1). Plasma and urine will be collected in a manner identical to that in Arm 1. With respect to midazolam administration, a washout period of 7 days will separate Arm 2 from Arm 1. | Drug: Midazolam Hcl 1Mg/Ml Inj<br>* 0.5 mL of an intravenous solution (1 mg/mL) will be administered.<br>* Other names: Versed;Dietary Supplement: Goldenseal (Hydrastis canadensis)<br>* Goldenseal (Solaray; Lot #1020199) is supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules will be administered with 240 mL of water.<br>|
| Experimental: Study Arm 3: Chronic Goldenseal Exposure<br>For Arm 3, the same 20 subjects will be administered goldenseal (1.1 g) orally three times daily for 27 days. On the 28th day, participants will be administered the goldenseal three times daily, as well as the single dose of midazolam (as described in Arm 1). Plasma and urine will be collected in a manner identical to that in Arm 1. A designated washout period for midazolam will not be necessary to separate Arm 3 from Arm 2 since there will be 27 days of goldenseal administration prior to the midazolam administration. | Drug: Midazolam Hcl 1Mg/Ml Inj<br>* 0.5 mL of an intravenous solution (1 mg/mL) will be administered.<br>* Other names: Versed;Dietary Supplement: Goldenseal (Hydrastis canadensis)<br>* Goldenseal (Solaray; Lot #1020199) is supplied as dried root powder in vegetable capsules, each containing 550 mg of herbal content. Goldenseal capsules will be administered with 240 mL of water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metformin area under the concentration vs. time curve (AUC) ratio (exposure/baseline) | Ratio of the area under the plasma concentration time curve (AUC) of metformin in the presence to absence of goldenseal. | 0-24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Midazolam area under the concentration vs. time curve (AUC) ratio (exposure/baseline) | Ratio of the area under the plasma concentration time curve (AUC) of midazolam in the presence to absence of goldenseal. | 0-24 hours | 
| Metformin Cmax ratio (exposure/baseline) | Ratio of the maximum plasma concentration (Cmax) of metformin in the presence to absence of goldenseal. | 0-24 hours | 
| Midazolam Cmax ratio (exposure/baseline) | Ratio of the maximum plasma concentration (Cmax) of midazolam in the presence to absence of goldenseal. | 0-24 hours | 
| Metformin half-life ratio (exposure/baseline) | Ratio of the time to reach one-half of the concentration of metformin in the presence to absence of goldenseal. | 0-24 hours | 
| Midazolam half-life ratio (exposure/baseline) | Ratio of the time to reach one-half of the concentration of midazolam in the presence to absence of goldenseal. | 0-24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, natural product-drug interactions, transporters