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

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

View full results

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

COMPLETED

Clinical Phase

EARLY_PHASE1

Total Enrollment

16 participants

Study Classification

INTERVENTIONAL

Study Start Date

2022-04-11

Study Completion Date

2023-07-22

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

This Study Tests the Effect of Certain Medicines on the Transport of Other Medicines in the Body of Healthy Men

NCT03307252

Healthy

COMPLETED PHASE1

A Study to Assess the Effects of Savolitinib on the Pharmacokinetics of Digoxin, Rosuvastatin, Metformin, and Furosemide in Healthy Male Subjects

NCT05768360

Healthy Male Subjects

COMPLETED PHASE1

Influence of Fedratinib on the Pharmacokinetics of the Transporter Probe Substrates Digoxin, Rosuvastatin, and Metformin

NCT04231435

Healthy Volunteers

COMPLETED PHASE1

Study to Evaluate the Effect of Repotrectinib on the Drug Levels of Transporter and CYP P450 Probe Substrates in Healthy Adult Participants

NCT07223671

Healthy Volunteers

RECRUITING PHASE1

Drug-drug Interaction Between Digoxin, Furosemide, Metformin, and Rosuvastatin

NCT02231931

Healthy

COMPLETED PHASE1

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

Interaction Endogenous Biomarkers

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NON_RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Study Groups

Review each arm or cohort in the study, along with the interventions and objectives associated with them.

Arm 2B: furosemide + probenecid

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.

Group Type EXPERIMENTAL

Furosemide Oral Liquid Product

Intervention Type DRUG

oral solution

Probenecid 500 MG

Intervention Type DRUG

tablet

Arm 1A: metformin alone (baseline)

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.

Group Type EXPERIMENTAL

MetFORMIN Oral Solution

Intervention Type DRUG

liquid

Arm 1B: metformin + cimetidine

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.

Group Type EXPERIMENTAL

MetFORMIN Oral Solution

Intervention Type DRUG

liquid

Cimetidine 400 MG

Intervention Type DRUG

tablet

Arm 2A: furosemide alone (baseline)

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.

Group Type EXPERIMENTAL

Furosemide Oral Liquid Product

Intervention Type DRUG

oral solution

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

MetFORMIN Oral Solution

liquid

Intervention Type DRUG

Cimetidine 400 MG

tablet

Intervention Type DRUG

Furosemide Oral Liquid Product

oral solution

Intervention Type DRUG

Probenecid 500 MG

tablet

Intervention Type DRUG

Other Intervention Names

Discover alternative or legacy names that may be used to describe the listed interventions across different sources.

Riomet Tagamet Lasix Probalan

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

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

Minimum Eligible Age

18 Years

Maximum Eligible Age

65 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes