Microbial Colonization
Conditions
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.
Interventions
DRUGTolcapone 100 MG
Tolcapone 100 mg by mouth once
DRUGDuloxetine 20 MG
Duloxetine 20 mg by mouth once
Sponsors
Rutgers, The State University of New Jersey
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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 * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Drug area under the plasma concentration versus time curve (AUC) | 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 peak plasma concentration | 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 |
| Drug trough plasma concentrations | 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 volume of distribution | 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 | 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 | 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. |
Countries
United States
Outcome results
None listed