Microbiome Derived Metabolism and Pharmacokinetics

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Incorporating Drug Metabolism by the Human Gut Microbiome Into Personalized Medicine

Conditions
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Microbial Colonization

Intervention / Treatment
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* Drug: Tolcapone 100 MG
* Drug: Duloxetine 20 MG


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tolcapone<br>Tolcapone 100 mg by mouth once | Drug: Tolcapone 100 MG<br>* Tolcapone 100 mg by mouth once<br>|
| Experimental: Duloxetine<br>Duloxetine 20 mg by mouth once | Drug: Duloxetine 20 MG<br>* Duloxetine 20 mg by mouth once<br>|

What is the study measuring?
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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) |