Microbiome Influence on Drug Metabolism

(MDM-PK Trial)

Overseen By Mohamed Donia, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Rutgers, The State University of New Jersey

Must not be taking: Antibiotics, Immune modulators

Disqualifiers: Gastrointestinal, Autoimmune, Viral, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

14 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators will perform single-dose pharmacokinetic (PK) studies in humans following administration of drugs with known microbiome derived metabolism (MDM) in parallel with preclinical studies. By directly comparing laboratory measurements to clinical results, the investigators will be able to confirm the relevance of MDM in vivo, create microbiome-dependent PK profiles of the MDM positive drugs, and establish methodology to capture the contribution of MDM to inter-individual variability in clinical drug PK profiles.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you use immune modulating medications or have any contraindications to the study medications.

What data supports the effectiveness of the drug Duloxetine in relation to gut microbiome interactions?

Research shows that gut bacteria can affect how drugs like Duloxetine work in the body by storing the drug and altering its availability, which can change how effective the drug is and how it affects the body. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Duloxetine, known by various names like Cymbalta, is generally safe and well-tolerated for conditions like depression and pain, with few serious side effects. Common side effects are related to the stomach and nervous system, and it should not be combined with certain other medications. ^{6 7 8 9 10}

How does the drug Duloxetine differ from other treatments for its condition?

This drug is unique because it considers the influence of gut bacteria on drug metabolism, which can affect how well the drug works and its side effects. The study of Duloxetine's interaction with gut microbiota is novel, as it explores how bacteria can store the drug and alter its availability and effectiveness, potentially leading to more personalized treatment outcomes. ^{1 3 4 11 12}

Eligibility Criteria

This trial is for healthy adults aged 18-65 with a BMI of 18.5-29.9 kg/m2 who haven't taken antibiotics in the last 3 months, don't smoke, and have no history of gastrointestinal disease or chronic viral infections. They should not be heavy drinkers or have liver impairment, diabetes, autoimmune disorders, or any contraindications to study medications.

Inclusion Criteria

Body mass index between 18.5 - 29.9 kg/m2

Exclusion Criteria

Smoker

My kidney function is reduced with a creatinine clearance below 50 mL/min.

I am taking medication that affects my immune system.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of either Tolcapone or Duloxetine to study microbiome-derived metabolism

1 day

1 visit (in-person)

Pharmacokinetic Analysis

Measurement of drug metabolites, volume of distribution, plasma concentrations, clearance, half-life, and AUC over an 8-hour period

8 hours

Continuous monitoring during the visit

Follow-up

Participants are monitored for any adverse effects and overall safety after the pharmacokinetic study

1-2 weeks

Treatment Details

Interventions

• Duloxetine 20 MG
• Duloxetine 30 MG
• Tolcapone 100 MG

Trial Overview The study tests how the body processes Tolcapone and Duloxetine—drugs affected by gut bacteria—by comparing lab results with those from human participants. The goal is to understand individual differences in drug metabolism due to microbiome interactions.

Participant Groups

Group I: Tolcapone Experimental Treatment 1 Intervention

Tolcapone 100 mg by mouth once

Group II: Duloxetine Experimental Treatment 1 Intervention

Duloxetine 20 mg by mouth once

Duloxetine 20 MG is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cymbalta for:

• Major depressive disorder
• Generalized anxiety disorder
• Fibromyalgia
• Neuropathic pain
• Chronic musculoskeletal pain

Approved in European Union as Cymbalta for:

• Major depressive disorder
• Generalized anxiety disorder
• Diabetic neuropathic pain
• Fibromyalgia

Approved in Canada as Cymbalta for:

• Major depressive disorder
• Generalized anxiety disorder
• Diabetic neuropathic pain
• Fibromyalgia
• Chronic musculoskeletal pain

Who Is Running the Clinical Trial?

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

Findings from Research

This study identified 70 interactions between gut bacteria and 15 different drugs, including 29 new interactions, highlighting the significant role of gut bacteria in drug metabolism and efficacy.

Specifically, the antidepressant duloxetine was found to be bioaccumulated by certain gut bacteria, which altered the bacteria's metabolism and affected the drug's impact on behavior in an animal model, suggesting that gut bacteria can influence drug responses and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioaccumulation of therapeutic drugs by human gut bacteria. Klünemann, M., Andrejev, S., Blasche, S., et al.[2023]

This study developed an ex vivo fermentation screening platform to investigate how human colon microbiota metabolize drugs, using a set of 12 different medications under strictly controlled anaerobic conditions.

Out of the 12 drugs tested, five (sulfasalazine, sulfinpyrazone, sulindac, nizatidine, and risperidone) were found to undergo significant microbiota-based biotransformation, indicating that gut bacteria can influence drug metabolism and potentially affect drug efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Ex Vivo Fermentation Screening Platform to Study Drug Metabolism by Human Gut Microbiota. van de Steeg, E., Schuren, FHJ., Obach, RS., et al.[2019]

A 7-day course of the antibiotic cefprozil was found to decrease the activity of important liver enzymes (CYP1A2, CYP2C19, and CYP3A) that are crucial for drug metabolism, indicating potential impacts on how other medications are processed in the body.

The study also revealed that cefprozil reduced the diversity of gut microbiomes, which correlated with increased variability in drug and metabolite formation, suggesting that antibiotics can significantly alter drug metabolism and efficacy on an individual level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study. Jarmusch, AK., Vrbanac, A., Momper, JD., et al.[2023]

Gut microbiota can significantly influence the metabolism of orally administered drugs, either inactivating them or activating prodrugs, depending on the specific drug and the individual's microbiota composition.

Factors such as diet, antibiotics, probiotics, and stress can alter gut microbiota, which in turn affects the bioavailability and effectiveness of medications, highlighting the importance of understanding these interactions for optimizing drug therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction of drugs with gut microbiota modulators. Kim, DH.[2023]

The gut microbiota significantly influences drug metabolism, affecting how drugs are processed before absorption and during enterohepatic circulation, which can alter their effectiveness and safety.

Some drugs are metabolized by gut bacteria into specific metabolites that the liver cannot produce, highlighting the importance of understanding gut microbiota's role in drug pharmacokinetics and potential toxicities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs. Noh, K., Kang, YR., Nepal, MR., et al.[2018]

Escitalopram, duloxetine, and gepirone are new antidepressant agents that undergo significant biotransformation, primarily involving cytochrome P450 (CYP) enzymes, which can affect their efficacy and safety.

Polymorphisms in the CYP2C19 enzyme and interactions with CYP2D6 can lead to clinically significant variations in how patients respond to escitalopram and duloxetine, highlighting the importance of personalized medicine in treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolism of the newest antidepressants: comparisons with related predecessors. Caccia, S.[2015]

Duloxetine is effective for various conditions, including major depressive disorder and diabetic neuropathic pain, with a maximum plasma concentration reached about 6 hours after dosing, highlighting its pharmacokinetic profile.

Factors such as hepatic function and certain medications can significantly impact duloxetine's effectiveness and safety, particularly CYP1A2 inhibitors which can increase its concentration by up to 460%, necessitating careful monitoring and potential dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine: clinical pharmacokinetics and drug interactions. Knadler, MP., Lobo, E., Chappell, J., et al.[2022]

A study of 2,004 patients prescribed duloxetine found that urinary concentrations of the medication ranged from 50 to 2,722 ng/mL, providing a baseline for monitoring patient adherence.

Urinary duloxetine concentrations varied significantly by sex and dosage, with notable differences in female patients across different age groups, indicating that these factors should be considered when assessing compliance in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of Patient Adherence for Duloxetine in Urine. Mulder, HA., McIntire, GL., Wallace, FN., et al.[2023]

Duloxetine is a safe and well-tolerated medication for treating major depressive disorder, diabetic neuropathic pain, and female stress urinary incontinence, with few serious side effects reported.

While it can be prescribed at doses up to 400 mg/day, the approved maximum is 120 mg/day, and it primarily affects the metabolism of certain drugs, particularly inhibiting CYP 2D6, which is important for clinicians to consider when prescribing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and adverse event profile of duloxetine. Wernicke, JF., Gahimer, J., Yalcin, I., et al.[2022]

Duloxetine is an effective treatment for major depressive disorder (MDD), showing significant improvements in both emotional and painful physical symptoms, with noticeable effects after just 1-2 weeks at a dosage of 60 mg per day.

In terms of efficacy, duloxetine is comparable to other antidepressants like paroxetine and escitalopram over both short-term (up to 15 weeks) and longer-term (6-8 months) treatments, and it is generally well tolerated, although starting at 60 mg/day may lead to higher discontinuation rates due to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine: a review of its use in the treatment of major depressive disorder. Frampton, JE., Plosker, GL.[2018]

Antidepressants can significantly alter the composition of intestinal microbiota, which may affect how well these medications work for treating depression.

The interactions between intestinal microbiota and antidepressants can influence drug metabolism, absorption, and even the permeability of the blood-brain barrier, suggesting that targeting gut microbiota could enhance depression treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions Between Antidepressants and Intestinal Microbiota. Xu, F., Xie, Q., Kuang, W., et al.[2023]

The human microbiome significantly influences drug metabolism, toxicity, and efficacy, particularly for chemotherapeutic agents and immunotherapies, highlighting its potential as a target for drug development.

Research using germ-free or microbiome-depleted animal models shows that specific bacterial species can alter drug metabolism, suggesting that understanding these interactions could lead to more effective and personalized drug therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Microbiota-drug interactions: Impact on metabolism and efficacy of therapeutics. Wilkinson, EM., Ilhan, ZE., Herbst-Kralovetz, MM.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Bioaccumulation of therapeutic drugs by human gut bacteria. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

An Ex Vivo Fermentation Screening Platform to Study Drug Metabolism by Human Gut Microbiota. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Enhanced Characterization of Drug Metabolism and the Influence of the Intestinal Microbiome: A Pharmacokinetic, Microbiome, and Untargeted Metabolomics Study. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Interaction of drugs with gut microbiota modulators. [2023]

5. Korea (South) pubmed.ncbi.nlm.nih.gov

Impact of gut microbiota on drug metabolism: an update for safe and effective use of drugs. [2018]

6. England pubmed.ncbi.nlm.nih.gov

Metabolism of the newest antidepressants: comparisons with related predecessors. [2015]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Duloxetine: clinical pharmacokinetics and drug interactions. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Determination of Patient Adherence for Duloxetine in Urine. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Safety and adverse event profile of duloxetine. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Duloxetine: a review of its use in the treatment of major depressive disorder. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Interactions Between Antidepressants and Intestinal Microbiota. [2023]

12. Ireland pubmed.ncbi.nlm.nih.gov

Microbiota-drug interactions: Impact on metabolism and efficacy of therapeutics. [2018]