Clinical trial NCT05065671: Microbiome Derived Metabolism and Pharmacokinetics
Official title: Incorporating Drug Metabolism by the Human Gut Microbiome Into Personalized Medicine
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Microbial Colonization
Lead sponsor: Rutgers, The State University of New Jersey
Sponsor class: OTHER
First posted: 2021-10-04
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

Eligibility 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)

Primary outcomes:
measure: Drug area under the plasma concentration versus time curve (AUC)
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Drug peak plasma concentration
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Drug trough plasma concentrations
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Drug volume of distribution
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Drug half-life
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Drug plasma clearance
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Secondary outcomes:
Other outcomes:
measure: Quantitation of microbiome derived metabolism positive drug metabolites in urine
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
measure: Quantitation of microbiome derived metabolism positive drugs in urine
timeFrame: After a single dose of a microbiome derived metabolism positive drug (over an 8 hour period for each drug)
Locations:
city: Somerville
country: United States
facility: Robert Wood Johnson University Hospital Somerset
state: New Jersey
Study officials:
References: