Microbiome Derived Metabolism and Pharmacokinetics (MDM-PK)

Incorporating Drug Metabolism by the Human Gut Microbiome Into Personalized Medicine

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.

Study Overview

• Status: Completed
• Conditions: Microbial Colonization
• Intervention / Treatment: Drug: Tolcapone 100 MG; Drug: Duloxetine 20 MG

Detailed Description

The human gut microbiome has been shown to play an important role in the observed inter-individual variability in therapeutic response, including both efficacy and toxicity. One of the mechanisms by which the gut microbiome exerts these effects is through the direct biochemical transformation of orally administered drugs into more or less active or toxic metabolites, termed herein microbiome-derived drug metabolism (MDM). Recent systematic studies have revealed an enormous and largely unexplored biochemical capacity of human gut bacteria - cultured in ex vivo microbial communities or as single isolates - to metabolize dozens of orally administered drugs but the clinical relevance of the observed MDM remains unmapped. This gap in knowledge is a result of overt disconnect between preclinical and clinical studies: MDM studies performed in the laboratory are removed from direct clinical comparisons, and human studies performed during drug development and therapeutic interventions almost completely ignore microbiome contribution. Moreover, there is currently a lack standardized experimental methods and mathematical models to start incorporating MDM into clinical decisions. Our PK studies are aimed at developing such strategies into clinical practice.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Somerville, New Jersey, United States, 08876
      • Robert Wood Johnson University Hospital Somerset

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 18 to 65 years of age
• Body mass index between 18.5 - 29.9 kg/m2

Exclusion Criteria

• Estimated creatinine clearance < 50 mL/min
• Liver impairment (liver enzymes > 2 times upper limit)
• Antibiotics in the past 3 months
• History of gastrointestinal disease
• History of autoimmune disorder
• Chronic viral infection
• Smoker
• Alcohol intake (defined as having up to 1 drink per day for women and up to 2 drinks per day for men)
• Use of immune modulating medications
• Diabetes mellitus
• Any history or contraindication to the study medications
• Additional exclusion criteria will be based on the FDA approved prescribing information for selected drugs (i.e., contraindications)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tolcapone; Tolcapone 100 mg by mouth once	Drug: Tolcapone 100 MG; Tolcapone 100 mg by mouth once
Experimental: Duloxetine; Duloxetine 20 mg by mouth once	Drug: Duloxetine 20 MG; Duloxetine 20 mg by mouth once

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug area under the plasma concentration versus time curve (AUC)	We will calculate the plasma area under the curve for the microbiome derived metabolism positive probe drugs	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Drug peak plasma concentration	We will measure the peak plasma concentration for microbiome derived metabolism positive probe drugs	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Drug trough plasma concentrations	We will measure the trough plasma concentration for microbiome derived metabolism positive probe drugs	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Drug volume of distribution	We will calculate the volume of distribution for microbiome derived metabolism positive probe drugs	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Drug half-life	We will calculate drug half-life for microbiome derived metabolism positive probe drugs	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Drug plasma clearance	We will calculate drug plasma clearance for each microbiome derived metabolism positive drug.	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitation of microbiome derived metabolism positive drug metabolites in urine	The concentration of microbiome derived metabolism positive drug metabolites in urine will be measured	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Quantitation of microbiome derived metabolism positive drugs in urine	The concentration of microbiome derived metabolism positive drugs in urine will be measured.	After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Actual): September 23, 2025
• Study Completion (Actual): September 23, 2025

Study Registration Dates

• First Submitted: September 13, 2021
• First Submitted That Met QC Criteria: September 22, 2021
• First Posted (Actual): October 4, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Infections; Pathological Conditions, Signs and Symptoms; Communicable Diseases; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Phenols; Benzene Derivatives; Nitro Compounds; Thiophenes; Ketones; Benzophenones; Nitrophenols; Duloxetine Hydrochloride; Tolcapone
• Other Study ID Numbers: Pro2021000945

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No