Pharmacokinetic Drug-Drug Interaction Study to Identify Biomarkers of Kidney Transporters

Study Overview
=================
Brief Summary
-----------------
The objective of this study is to confirm the feasibility of using a panel of endogenous substrates/metabolites as a robust biomarker of OCTs and OATs by conducting a controlled, comprehensive clinical drug-drug interaction study in healthy adult volunteers. Metformin and furosemide will be used as probe drugs for OCTs and OATs, respectively; cimetidine and probenecid will be used as corresponding inhibitors. Results from this study will validate this novel approach, which will be extended to children by collaborators at Children's Mercy Hospital in Kansas City, MO.

Detailed Description
-----------------
The kidneys are major organs responsible for the excretion of both endogenous and exogenous compounds, the latter including drugs and other xenobiotics. Excretion occurs via passive or active processes, the latter involving transporters such as organic cation transporters (OCTs) and organic anion transporters (OATs). Inhibition of these transporters, coupled with the large interindividual variability in transporter expression, can lead to toxic accumulation of compounds/xenobiotics cleared primarily by this route. During drug discovery and development, if in vitro evidence suggests renal transporters mediate excretion of a new chemical entity, the Food and Drug Administration recommends conducting a controlled clinical study to evaluate potential risks. These time-consuming and expensive clinical studies routinely involve adult participants and known substrates of renal transporters. However, such studies are not always feasible in children due to the enhanced potential for toxicities. This limitation led to the hypothesis that endogenous substrates could be used as surrogates, or biomarkers, of individual renal transporter function. Endogenous OCT substrates, such as 1-methyladenosine (m1A) and 1-methylnicotinamide (MNA), as well as OATs, such as homovanillic acid (HVA) and pyridoxic acid (PDA), are promising biomarkers of renal transporters in adults. However, using one or few such endogenous substrates can be misleading due to factors other than variability in specific renal transporter function. We propose to address this knowledge gap by using a panel of endogenous substrates/metabolites that recently has been identified as a robust biomarker of rodent Octs and Oats. Validation of these substrates/metabolites as biomarkers of OCTs and OATs in humans, both adults and children, will aid in the development of physiologically-based pharmacokinetic models that can be used to predict renal transporter-mediated xenobiotic excretion, drug-drug interactions, and toxicity in children.

Official Title
-----------------
Pharmacokinetic Drug-Drug Interaction Study to Identify Biomarkers of Kidney Transporters

Conditions
-----------------
Interaction, Endogenous Biomarkers

Intervention / Treatment
-----------------
* Drug: MetFORMIN Oral Solution
* Drug: Cimetidine 400 MG
* Drug: Furosemide Oral Liquid Product
* Drug: Probenecid 500 MG


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Are from 18-65 years old and healthy Are not taking any medications (prescription and non-prescription) or dietary/herbal supplements that can interfere with your ability to eliminate the study drugs from your body Are willing to stop taking dietary/herbal supplements and citrus juices for several weeks Are willing to stop consuming caffeinated beverages or other caffeine-containing products the evening before and the morning of the first day of each study arm Are willing to stop drinking alcoholic beverages for at least 1 day prior to any study day and during the study day Are willing to use an acceptable method of birth control that does not include oral contraceptive pills or patches (such as abstinence, copper IUD, condom) throughout your participation in the study and for at least 3 weeks after you last take the study drugs Have the time to participate Exclusion Criteria: Are under 18 or over 65 years old Smoke/vape/chew tobacco products Use cannabis products, including marijuana, hemp, and other THC- and CBDcontaining products• Are taking medications or dietary/herbal supplements that can interfere with your ability to eliminate the study drugs from your body Have a chronic illness such as (but not limited to) kidney disease, liver disease, diabetes mellitus, high blood pressure, coronary artery disease, chronic obstructive pulmonary disease, cancer, or HIV/AIDS Have a hematologic (blood) disorder Have a history of drug or alcohol addiction or major psychiatric illness Have a history of allergy to metformin, cimetidine, furosemide, or probenecid Are pregnant, nursing, or plan to become pregnant within 3 weeks after participation

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1A: metformin alone (baseline)<br>Arm 1A will consist of administration of a single dose of metformin (50 mg) by mouth as a liquid to 16 subjects (8 males, 8 females). Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 2A and 2B. A washout of at least 7 days will occur between Arm 1A and Arm 1B. | Drug: MetFORMIN Oral Solution<br>* liquid<br>* Other names: Riomet;|
| Experimental: Arm 1B: metformin + cimetidine<br>Arm 1B will consist of administration of a single oral dose of cimetidine (400 mg) with water by mouth. One hour later, metformin (50 mg) will be administered by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 2A and 2B. A washout of at least 7 days will occur between Arm 1B and Arm 2A. | Drug: MetFORMIN Oral Solution<br>* liquid<br>* Other names: Riomet;Drug: Cimetidine 400 MG<br>* tablet<br>* Other names: Tagamet;|
| Experimental: Arm 2A: furosemide alone (baseline)<br>Arm 2A will consist of administration of a single dose of furosemide (5 mg) by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. A washout of at least 7 days will occur between Arm 2A and Arm 2B. | Drug: Furosemide Oral Liquid Product<br>* oral solution<br>* Other names: Lasix;|
| Experimental: Arm 2B: furosemide + probenecid<br>Arm 2B will consist of administration of a single oral dose of probenecid (1,000 mg) with water by mouth. One hour later, furosemide (5 mg) will be administered by mouth as a liquid. Plasma and urine will be collected from 0-24 hours. Participants may or may not elect to participate in Arms 1A and 1B. A washout of at least 7 days will occur between Arm 2B and Arm 1A. | Drug: Furosemide Oral Liquid Product<br>* oral solution<br>* Other names: Lasix;Drug: Probenecid 500 MG<br>* tablet<br>* Other names: Probalan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metformin area under the concentration vs. time curve (AUC) | baseline metformin AUC | 0-24 hours | 
| Metformin area under the concentration vs. time curve (AUC) in presence of cimetidine | metformin AUC in the presence of cimetidine | 0-24 hours | 
| Metformin maximum concentration (Cmax) | baseline metformin Cmax | 0-24 hours | 
| Metformin maximum concentration (Cmax) in presence of cimetidine | metformin Cmax in the presence of cimetidine | 0-24 hours | 
| Metformin renal clearance (CLr) | baseline metformin CLr | 0-24 hours | 
| Metformin renal clearance (CLr) in presence of cimetidine | metformin CLr in the presence of cimetidine | 0-24 hours | 
| Furosemide area under the concentration vs. time curve (AUC) | baseline furosemide AUC | 0-24 hours | 
| Furosemide area under the concentration vs. time curve (AUC) in presence of probenecid | furosemide AUC in the presence of probenecid | 0-24 hours | 
| Furosemide maximum concentration (Cmax) | baseline furosemide Cmax | 0-24 hours | 
| Furosemide maximum concentration (Cmax) in presence of probenecid | furosemide Cmax in the presence of probenecid | 0-24 hours | 
| Furosemide renal clearance (CLr) | baseline furosemide CLr | 0-24 hours | 
| Furosemide renal clearance (CLr) in presence of probenecid | furosemide CLr in the presence of probenecid | 0-24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Kidney Transporter, Pharmacokinetics