Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product

Study Overview
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Brief Summary
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Kratom is a botanical natural product that has opioid-like effects. Kratom is commonly used to self-treat withdrawal symptoms associated with opioid addiction, as well as pain. Kratom products include pills, extracts, and powders, most of which contain two primary psychoactive constituents: mitragynine and 7-hydroxymitragynine. Preliminary data from the investigator's laboratory has shown that these two constituents and extracts made from commercially available kratom products are strong inhibitors of the drug metabolizing enzymes cytochrome P450 (CYP) 2D6 and CYP3A4. These enzymes are responsible for metabolizing more than 50% of marketed drugs, including several opioids, benzodiazepines, and antidepressants. Thus, co-consumption of kratom products with drugs metabolized by CYP2D6 and CYP3A4 could increase the risk of serious adverse effects. The effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity will be assessed in healthy volunteers using a 'cocktail' approach consisting of the validated probe drugs dextromethorphan and midazolam. Results will (1) provide useful information regarding risks associated with co-consuming kratom with opioids and other CYP2D6 and CYP3A4 drug substrates and (2) inform the design of future kratom-drug interactions studies.

Detailed Description
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Many patient groups often supplement their drug regimens with herbal and other natural products (NPs), raising concern for adverse NP-drug interactions. Due to a lack of rigorous guidelines for assessing the risk of NP-drug interactions, the NIH-funded Center of Excellence for Natural Product-Drug Interaction Research (NaPDI Center) was established to facilitate the identification, evaluation, and dissemination of potentially clinically relevant pharmacokinetic NP-drug interactions.Kratom is one of four high priority NPs selected by the NaPDI Center for rigorous study of drug interaction potential. Kratom (Mitragyna speciosa) is a tree native to Southeast Asia that produces constituents with opioid-like effects. Oral supplements made from the leaves are readily available in the United States and are used for several purported medicinal benefits, such as pain relief, treatment of post-traumatic stress disorder, and management of opioid addiction. Two psychoactive constituents of the kratom leaf, mitragynine and 7- hydroxymitragynine, are believed to contribute to these effects. Calls to poison control centers in the United States involving kratom exposures increased from 2011 to 2017 by 52-fold. More than one-third of the calls reported combined use of kratom with other substances, including opioids and benzodiazepines. In October 2017, the opioid crisis was declared a public health emergency. Many opioids are metabolized by the major drug metabolizing enzymes CYP2D6 and CYP3A4, which have been shown to be inhibited by an extract prepared from a well-characterized kratom product and purified major kratom constituents, including mitragynine and 7-hydroxymitragynine. As such, co-consuming kratom with these opioids could increase the risk of serious adverse effects via inhibition of opioid metabolism, notably respiratory depression, the primary cause of death from opioid overdose. The purpose of this study is to assess the effects of a well-characterized kratom product on CYP2D6 and CYP3A4 activity in healthy volunteers using a cocktail approach consisting of the validated probe drugs dextromethorphan and midazolam. The primary objective is to evaluate the potential for a pharmacokinetic kratom-drug interaction with midazolam, a 'probe' drug for CYP3A4, when administered to participants previously exposed to kratom. Secondary objectives are to evaluate the pharmacokinetics of kratom constituents and the effect of kratom on the pharmacokinetics of dextromethorphan, a probe drug for CYP2D6. Results will be used to develop physiologically-based pharmacokinetic (PBPK) models to predict the likelihood and magnitude of kratom-drug interactions, including those involving opioids. These PBPK models could be adapted to other CYP2D6 and CYP3A4 drug substrates with high abuse potential (e.g., benzodiazepines and 'Z-drugs') and used to inform the design of future kratom-drug interactions studies.

Official Title
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Assessing the Pharmacokinetics and Drug Interaction Liability of Kratom, an Opioid-like Natural Product

Conditions
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Interaction Drug Food

Intervention / Treatment
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* Drug: Midazolam HCl
* Drug: Dextromethorphan HBr
* Dietary Supplement: Kratom


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Not taking any medications (prescription and non-prescription) or dietary/herbal supplements known to alter the pharmacokinetics of either study drug or kratom constituents Willing to abstain from consuming dietary/herbal supplements, including kratom, and citrus juices for several weeks Willing to abstain from consuming caffeinated beverages or other caffeine-containing products the evening before and morning of the first day of a study arm Willing to abstain from consuming any alcoholic beverages for one day prior to any study day, during the 14-hour inpatient days, and for the 5 and/or 1 outpatient visit(s) following 14-hour visit Willing to use an acceptable method of contraception that does not include oral contraceptive pills or patches (such as abstinence, copper IUD, condom) Have the time to participate Are non-naïve kratom users (intermittent users who are not trying to quit but willing to abstain for several weeks) Carry a CYP2D6 genotype designated as having an intermediate, extensive, or ultra-extensive metabolizer phenotype 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: Men and women under the age of 18 or over the age of 55 Unwilling to abstain from kratom for several weeks Any current major illness or chronic illness such as (but not limited to) kidney disease, hepatic disease, diabetes mellitus, hypertension, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS History of anemia or any other significant hematologic disorder History of drug or alcohol addiction or major psychiatric illness A need for chronic opioid analgesics Use of opioid analgesics 3 weeks prior to initiation of the study An imminent likely need for opioid analgesics (e.g., planned dental or surgical procedure) Female and pregnant or nursing Have a history of allergy to dextromethorphan, midazolam, or related drugs Have a history of intolerance or allergy to kratom or opioids Taking concomitant medications, both prescription and non-prescription (including dietary supplements/herbal products), known to alter the pharmacokinetics of either study drug or kratom constituents Carry a CYP2D6 genotype designated as having a poor metabolizer phenotype Presence of a condition or abnormality that, in the opinion of the Investigator, would compromise the safety of the patient or the quality of the data

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Six non-naive* subjects (3 males, 3 females) will be administered a single low dose of a well-characterized kratom product (2 g) by mouth as a tea. These subjects may or may not choose to participate in Arms 2a and 2b. For subjects who will participate in Arms 2a and 2b, a washout period of 7 days will separate Arm 1 and Arm 2. Plasma will be collected from 0-120 hours and during the washout period. Urine will be collected from 0-120 hours. *Non-naive subjects are defined as intermittent users who consume 2-8 g kratom at least once per month but no more than three times daily within the last six months prior to screening and are willing to abstain for several weeks. | Dietary Supplement: Kratom<br>* Kratom (Moon Kratom Yellow Indonesian, lot 51) is supplied as a dry leaf powder in clear plastic bags, each weighing 5 kg. Two g of kratom dry leaf powder will be stirred into 240 mL of hot water to make a tea. The tea will be cooled to 50 degrees Celsius before administration. Subjects will drink the tea within 10 minutes of administration.<br>|
| Experimental: Arm 2<br>Arm 2 is divided into Arms 2a and 2b. Twelve non-naive subjects (6 males, 6 females) will participate in Arm 2a. Subjects who participate in this study arm will be administered an oral probe drug cocktail of dextromethorphan HBr (2 x 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma will be collected from 0-24 hours. Urine will be collected from 0-24 hours. A washout period of 7 days will separate Arms 2a and 2b. For Arm 2b, the same 12 subjects will be administered a combination of a well-characterized kratom product (2 g) by mouth as a tea with an oral probe drug cocktail consisting of dextromethorphan HBr (2, 15 mg liquid capsules; 30 mg total) and midazolam HCl (1.25 mL of 2 mg/mL syrup; 2.5 mg total). Plasma will be collected from 0-12 hours and during a midpoint collection within 5 days of the 24-hour blood collection. Urine will be collected from 0-24 hours. | Drug: Midazolam HCl<br>* Oral syrup, 2 mg/mL<br>Drug: Dextromethorphan HBr<br>* Oral liquid capsules, 15 mg<br>Dietary Supplement: Kratom<br>* Kratom (Moon Kratom Yellow Indonesian, lot 51) is supplied as a dry leaf powder in clear plastic bags, each weighing 5 kg. Two g of kratom dry leaf powder will be stirred into 240 mL of hot water to make a tea. The tea will be cooled to 50 degrees Celsius before administration. Subjects will drink the tea within 10 minutes of administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Midazolam Area Under the Concentration vs. Time Curve (AUC) | Area under the plasma concentration time curve (AUC) of midazolam | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72 , 96, 120, and 144 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dextromethorphan Area Under the Concentration vs. Time Curve (AUC) | Area under the plasma concentration time curve (AUC) of dextromethorphan | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, 120, and 144 hours | 
| Mitragynine Area Under the Concentration vs. Time Curve (AUC) | Area under the concentration vs. time curve (AUC) of mitragynine. | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours | 
| Midazolam and Dextromethorphan Cmax | Maximum concentration (Cmax) of midazolam and dextromethorphan | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hours | 
| Mitragynine Cmax | Maximum plasma concentration of mitragynine. | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours | 
| Midazolam and Dextromethorphan Half-life | Time to reach one-half of the concentration of midazolam and dextromethorphan | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96,120, and 144 hours | 
| Mitragynine Half Life | Time to reach one-half of the concentration of mitragynine. | 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8,12, 24, 48, 72, 96, and 120 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Kratom, Mitragynine, Midazolam, Dextromethorphan, Natural product