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

Interaction Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05365451
• Other study ID #: 19163
• Secondary ID: R01HD081299
• Status: Completed
• Phase: Early Phase 1
• Start date: April 11, 2022
• Est. completion date: July 22, 2023

Study information

• Verified date: August 2023
• Source: Washington State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: July 22, 2023
• Est. primary completion date: July 22, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Interaction

Intervention

Drug:
• MetFORMIN Oral Solution
liquid
• Cimetidine 400 MG
tablet
• Furosemide Oral Liquid Product
oral solution
• Probenecid 500 MG
tablet

Locations

Country	Name	City	State
United States	Washington State University College of Pharmacy and Pharmaceutical Sciences	Spokane	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Washington State University	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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.

Outcome

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