Microbiome Derived Metabolism and Pharmacokinetics (MDM-PK)

Rutgers The State University of New Jersey

Status and phase: Enrolling; Phase 1

Conditions: Microbial Colonization

Treatments: Drug: Duloxetine 20 MG; Drug: Tolcapone 100 MG

Study type: Interventional

Funder types: Other

Identifiers

NCT05065671

Pro2021000945

Details and patient eligibility

About

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.

Full 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.

Enrollment: 14 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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)

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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14 participants in 2 patient groups

Tolcapone

Experimental group

Description:

Tolcapone 100 mg by mouth once

Treatment:

Drug: Tolcapone 100 MG

Duloxetine

Experimental group

Description:

Duloxetine 20 mg by mouth once

Treatment:

Drug: Duloxetine 20 MG