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

Early Phase 1

Completed

• Conditions: Interaction, Adverse Herb-Drug; Diabetes Mellitus, Type 2
• Interventions: Drug: Midazolam Hcl 1Mg/Ml Inj; Dietary Supplement: Goldenseal (Hydrastis canadensis)

• Registration Number: NCT05081583
• Lead Sponsor: Washington State University

Brief Summary

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

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.

Study Timeline

• Study Start: 2021-09-16
• Study First Submitted: 2021-10-04
• Study First Submitted QC: 2021-10-04
• Study First Posted: 2021-10-18
• Primary Completion: 2023-01-16
• Study Completion: 2023-08-31
• Results First Submitted: 2023-12-18
• Status Verified: 2024-12
• Results First Submitted QC: 2024-12-17
• Last Update Submitted: 2024-12-17
• Results First Posted: 2024-12-19
• Last Update Posted: 2024-12-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Study Arm 1: Baseline	Midazolam Hcl 1Mg/Ml Inj	An anticipated twenty type 2 diabetic subjects (10 males, 10 females) 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.
Study Arm 2: Acute Goldenseal Exposure	Midazolam Hcl 1Mg/Ml Inj	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.
Study Arm 3: Chronic Goldenseal Exposure	Midazolam Hcl 1Mg/Ml Inj	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.
Study Arm 2: Acute Goldenseal Exposure	Goldenseal (Hydrastis canadensis)	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.
Study Arm 3: Chronic Goldenseal Exposure	Goldenseal (Hydrastis canadensis)	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.

Primary Outcome Measures

Name	Time	Method
Metformin AUC	Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration.	Area under the plasma concentration time curve of metformin
Metformin Cmax	Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration.	maximum concentration of metformin

Secondary Outcome Measures

Name	Time	Method
Metformin Half-Life	0-24h	half-life of metformin
Metformin Renal Clearance	0-24h	renal clearance of metformin
Midazolam AUC	Before and 20 minutes, 40 minutes, and 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours after midazolam administration.	area under the concentration vs. time curve of midazolam

Trial Locations

Locations (1)

Washington State University College of Pharmacy and Pharmaceutical Sciences; 🇺🇸 Spokane, Washington, United States