Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach
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|ClinicalTrials.gov Identifier: NCT03772262|
Recruitment Status : Recruiting
First Posted : December 11, 2018
Last Update Posted : December 11, 2018
|Condition or disease||Intervention/treatment||Phase|
|Interaction Drug Food||Dietary Supplement: goldenseal Drug: Metformin Drug: Furosemide Drug: Midazolam oral solution Drug: Rosuvastatin Oral Tablet||Early Phase 1|
Many patient groups often supplement their pharmacotherapeutic regimens with herbal and other natural products (NPs), raising concern for adverse interactions with conventional drugs. Unlike for drug-drug interactions, rigorous guidelines for assessing the risk of NP-drug interactions do not exist. The NIH-funded Center of Excellence for Natural Product-Drug Interaction (NaPDI) Research (U54 AT008909) was created in September, 2015. The mission of the NaPDI Center is to provide leadership in the identification, evaluation, and dissemination of potential clinically significant pharmacokinetic NP-drug interactions. One over-arching goal of the Center is to develop a set of Recommended Approaches to guide researchers in the proper conduct of NP-drug interaction studies. These Recommended Approaches will be based on results generated from a series of Interaction Projects that will include mechanistic human in vitro and clinical studies focused on four carefully selected high priority NPs.
Using a systematic approach, the NaPDI Center selected four high priority NPs as precipitants of NP-drug interactions. One of these NPs is goldenseal, which is typically used to self-treat symptoms of the common cold, as well as numerous digestive disorders, both as a single extract and in combination with other NPs, particularly Echinacea spp. Major constituents of goldenseal include the isoquinoline alkaloids berberine, hydrastine, and hydrastinine. These constituents contain a methylenedioxyphenyl ring, a 'structural alert' that can lead to irreversible inhibition of drug metabolizing enzymes, particularly the cytochromes P450 (CYPs). Indeed, clinical studies involving healthy volunteers demonstrated that, compared to baseline (absence of goldenseal), CYP2D6 and CYP3A activities were reduced by 40-60% following administration of ~1 g of a goldenseal extract three times daily for 14 or 28 days .
Compared to the CYPs, the effects of goldenseal products on drug transporters are understudied, particularly in human subjects. A 'cocktail' consisting of 'probe' drug substrates for CYPs and transporters is an efficient, cost-effective means to examine the effects of a precipitant drug or NP on the pharmacokinetics of multiple object drugs simultaneously. Such cocktails are used frequently by both academia and the pharmaceutical industry to test for the interaction potential of new chemical entities, results of which are often included in drug labels. A number of cocktails exist for the CYPs and have been used successfully over the past 20+ years. A transporter cocktail was described recently that consists of the probe drugs furosemide [organic anion transporter (OAT)1 and OAT3 substrate], metformin [(organic cation transporter 2, multidrug and toxin extrusion protein (MATE)1, and MATE2-K substrate)], and rosuvastatin [organic anion transporting polypeptide (OATP)1B1, OATP1B3, and breast cancer resistance protein substrate].
Based on the multiple scientific gaps with respect to a commonly used NP, the purpose of this healthy volunteer study is to assess the inhibitory effects of a well-characterized goldenseal product on the pharmacokinetics of the aforementioned transporter probe drugs; the CYP3A probe midazolam will be included to serve as a positive control object drug. Results will be used to develop (1) a Recommended Approach regarding clinical study design of NP-drug interactions and (2) mathematical models that can be used to predict the risk of potential goldenseal-precipitated interactions with drugs whose pharmacokinetics are influenced by CYP3A and/or transporters.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||16 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Assessing Goldenseal-drug Interactions Using a Probe Drug Cocktail Approach|
|Actual Study Start Date :||April 5, 2018|
|Estimated Primary Completion Date :||November 30, 2018|
|Estimated Study Completion Date :||March 31, 2019|
Study subjects will be administered a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one rosuvastatin tablet (10 mg) by mouth. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.
Drug: Midazolam oral solution
Drug: Rosuvastatin Oral Tablet
Study subjects will be administered goldenseal 2 capsules (500 mg each) three times daily for 5 days. On day 6, subjects will be administered goldenseal 2 capsules (500 mg each), a single dose of midazolam syrup (2.5 mg), metformin solution (50 mg), furosemide solution (1 mg), and one tablet (10 mg) rosuvastatin. Goldenseal 2 capsules (500 mg each) will be administered approximately 4 and 8 hours later. Plasma will be collected from 0-96 hours. Urine will be collected from 0-24 hours.
Dietary Supplement: goldenseal
Oral 500 mg capsules
Drug: Midazolam oral solution
Drug: Rosuvastatin Oral Tablet
- midazolam AUC ratio (treatment/control) [ Time Frame: 0-96 hours ]ratio of the area under of the plasma concentration time curve (AUC) of midazolam in the presence to absence of goldenseal
- midazolam Cmax ratio (treatment/control) [ Time Frame: 0-96 hours ]ratio of the maximum plasma concentration (Cmax) of midazolam in the presence to absence of goldenseal
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03772262
|Contact: Mary F Paine, RPh, PhDfirstname.lastname@example.org|
|Contact: Deena Hadi, BSemail@example.com|
|United States, Washington|
|Washington State University||Recruiting|
|Spokane, Washington, United States, 99202|
|Contact: Malathi Jandhyala 509-335-3668 firstname.lastname@example.org|