Incorporating Drug Metabolism by the Human Gut Microbiome Into Personalized Medicine
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 14
- Locations
- 1
- Primary Endpoint
- Drug trough plasma concentrations
Study Overview
Brief Summary
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
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 Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
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
- •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)
Exclusion Criteria
- Not provided
Arms & Interventions
Tolcapone
Tolcapone 100 mg by mouth once
Intervention: Tolcapone 100 MG (Drug)
Duloxetine
Duloxetine 20 mg by mouth once
Intervention: Duloxetine 20 MG (Drug)
Outcomes
Primary Outcomes
Drug trough plasma concentrations
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will measure the trough plasma concentration for microbiome derived metabolism positive probe drugs
Drug area under the plasma concentration versus time curve (AUC)
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will calculate the plasma area under the curve for the microbiome derived metabolism positive probe drugs
Drug volume of distribution
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will calculate the volume of distribution for microbiome derived metabolism positive probe drugs
Drug half-life
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will calculate drug half-life for microbiome derived metabolism positive probe drugs
Drug plasma clearance
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will calculate drug plasma clearance for each microbiome derived metabolism positive drug.
Drug peak plasma concentration
Time Frame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
We will measure the peak plasma concentration for microbiome derived metabolism positive probe drugs
Secondary Outcomes
No secondary outcomes reported
Investigators
Luigi Brunetti
Associate Professor
Rutgers, The State University of New Jersey