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

NCT05365451 | Completed Early Phase 1 Results FDA Drug

• 2 other identifiers: 19163R01HD081299
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Interaction; Endogenous Biomarkers

Keywords

Kidney Transporter; Pharmacokinetics

Outcome Measures

Primary Outcomes (10)

• Metformin Area Under the Concentration vs. Time Curve (AUC)

  baseline metformin area under the concentration vs. time curve (AUC)

  0-24 hours

• Metformin AUC in Presence of Cimetidine

  Metformin area under the concentration vs. time curve (AUC) in presence of cimetidine

  0-24 hours

• Metformin Maximum Concentration (Cmax)

  baseline metformin maximum concentration (Cmax)

  0-24 hours

• Metformin Cmax in Presence of Cimetidine

  metformin Cmax in the presence of cimetidine

  0-24 hours

• Metformin Renal Clearance (CLr)

  baseline metformin renal clearance (CLr)

  0-24 hours

• Metformin 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 area under the concentration vs. time curve (AUC)

  0-24 hours

• Furosemide AUC in Presence of Probenecid

  furosemide AUC in the presence of probenecid

  0-24 hours

• Furosemide Renal Clearance (CLr)

  baseline furosemide renal clearance (CLr)

  0-24 hours

• Furosemide CLr in Presence of Probenecid

  furosemide CLr in the presence of probenecid

  0-24 hours

Study Arms (4)

Arm 1A: metformin alone (baseline)

EXPERIMENTAL

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

Arm 1B: metformin + cimetidine

EXPERIMENTAL

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; Drug: Cimetidine 400 MG

Arm 2A: furosemide alone (baseline)

EXPERIMENTAL

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

Arm 2B: furosemide + probenecid

EXPERIMENTAL

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; Drug: Probenecid 500 MG

Interventions

MetFORMIN Oral Solution DRUG

liquid

Also known as: Riomet

Arm 1A: metformin alone (baseline); Arm 1B: metformin + cimetidine

Cimetidine 400 MG DRUG

tablet

Also known as: Tagamet

Arm 1B: metformin + cimetidine

Furosemide Oral Liquid Product DRUG

oral solution

Also known as: Lasix

Arm 2A: furosemide alone (baseline); Arm 2B: furosemide + probenecid

Probenecid 500 MG DRUG

tablet

Also known as: Probalan

Arm 2B: furosemide + probenecid

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington State University: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Washington State University College of Pharmacy and Pharmaceutical Sciences

Spokane, Washington, 99202, United States

Location

Related Publications (6)

• Morrissey KM, Stocker SL, Wittwer MB, Xu L, Giacomini KM. Renal transporters in drug development. Annu Rev Pharmacol Toxicol. 2013;53:503-29. doi: 10.1146/annurev-pharmtox-011112-140317. Epub 2012 Nov 8.

  PMID: 23140242 BACKGROUND

• US Food and Drug Administration. Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.

  BACKGROUND

• Shen H, Holenarsipur VK, Mariappan TT, Drexler DM, Cantone JL, Rajanna P, Singh Gautam S, Zhang Y, Gan J, Shipkova PA, Marathe P, Humphreys WG. Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects. J Pharmacol Exp Ther. 2019 Jan;368(1):136-145. doi: 10.1124/jpet.118.252643. Epub 2018 Oct 25.

  PMID: 30361237 BACKGROUND

• Miyake T, Mizuno T, Takehara I, Mochizuki T, Kimura M, Matsuki S, Irie S, Watanabe N, Kato Y, Ieiri I, Maeda K, Ando O, Kusuhara H. Elucidation of N 1-methyladenosine as a Potential Surrogate Biomarker for Drug Interaction Studies Involving Renal Organic Cation Transporters. Drug Metab Dispos. 2019 Nov;47(11):1270-1280. doi: 10.1124/dmd.119.087262. Epub 2019 Sep 11.

  PMID: 31511257 BACKGROUND

• Naji-Talakar S, Sharma S, Martin LA, Barnhart D, Prasad B. Potential implications of DMET ontogeny on the disposition of commonly prescribed drugs in neonatal and pediatric intensive care units. Expert Opin Drug Metab Toxicol. 2021 Mar;17(3):273-289. doi: 10.1080/17425255.2021.1858051. Epub 2021 Jan 20.

  PMID: 33256492 BACKGROUND

• Feng B, Varma MV. Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions. J Clin Pharmacol. 2016 Jul;56 Suppl 7:S110-21. doi: 10.1002/jcph.702.

  PMID: 27385169 BACKGROUND

MeSH Terms

Interventions

Metformin; Cimetidine; Furosemide; Probenecid

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Sulfanilamides; Sulfonamides; Amides; Aniline Compounds; Amines; Sulfones; Sulfur Compounds

Results Point of Contact

• Title: Dr. Mary Paine
• Organization: Washington State University

mary.paine@wsu.edu

509-358-7759

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 4, 2022
• First Posted: May 9, 2022
• Study Start: April 11, 2022
• Primary Completion: July 22, 2023
• Study Completion: July 22, 2023
• Last Updated: August 8, 2025
• Results First Posted: August 8, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)