Combination Drugs for Drug Interactions

Overseen By Deena Hadi, BS

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Washington State University

Must not be taking: Prescription drugs, Supplements

Disqualifiers: Chronic illness, Tobacco, Cannabis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how different drugs interact in the body by using a set of natural markers. Participants will take metformin (for managing blood sugar levels) and furosemide (a diuretic), along with inhibitors like cimetidine (an acid reducer) and probenecid (used to treat gout), to observe their effects on drug processing. The study includes only healthy adults who are not taking medications or supplements and can adjust their diet and lifestyle during the trial. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a unique opportunity to contribute to foundational medical knowledge.

Will I have to stop taking my current medications?

Yes, you must stop taking any medications or supplements that could interfere with the study drugs. The trial requires participants to be medication-free to ensure accurate results.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that combining metformin with cimetidine can enhance metformin's effectiveness. Therefore, individuals using both medications should monitor their blood sugar levels more frequently. This combination also carries a risk of lactic acidosis, particularly for those with kidney issues.

Research suggests that furosemide and probenecid generally work well together and are easy to manage, with no major safety concerns reported.

Both drug combinations have been studied in controlled settings. While potential risks exist, careful monitoring and management can maintain safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore how common medications interact in the body, potentially leading to safer and more effective drug use. Unlike standard treatments that focus on individual drugs, this trial examines the effects of combining metformin with cimetidine and furosemide with probenecid. By understanding these interactions, researchers hope to optimize drug dosing and reduce side effects, which could revolutionize how we manage multiple medications. This approach is particularly promising for patients who take several drugs simultaneously, as it could lead to more personalized and precise treatment plans.

What evidence suggests that this trial's treatments could be effective?

Research has shown that cimetidine can affect how the body processes metformin, particularly in the kidneys. In this trial, one arm will study the combination of metformin and cimetidine to observe potential increases in metformin levels, which could pose risks for individuals with kidney problems. Another arm will examine the interaction between furosemide and probenecid. Studies have indicated that using furosemide with probenecid is a safe and reliable way to explore drug interactions. Furosemide helps remove excess fluid from the body, but its effectiveness might change when used with probenecid, which influences drug clearance by the kidneys. Researchers are studying each drug combination in separate arms to better understand their interactions. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

Healthy adults aged 18-65 who don't consume caffeine or alcohol before and during the study, aren't on interfering meds or supplements, can commit time to participate, and use certain birth control methods. Excluded are those under 18 or over 65, tobacco/cannabis users, pregnant/nursing women, with chronic illnesses like kidney disease or diabetes.

Inclusion Criteria

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 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

Exclusion Criteria

Are taking medications or dietary/herbal supplements that can interfere with your ability to eliminate the study drugs from your body

You use tobacco products like cigarettes, e-cigarettes, or chewing tobacco.

You use cannabis products, such as marijuana or hemp, that contain substances like THC and CBD.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment - Arm 1A: Metformin Alone

Administration of a single dose of metformin (50 mg) by mouth. Plasma and urine collected from 0-24 hours.

1 day

1 visit (in-person)

Washout Period

A washout period of at least 7 days between treatment arms to prevent drug interaction effects.

7 days

Treatment - Arm 1B: Metformin + Cimetidine

Administration of cimetidine (400 mg) followed by metformin (50 mg). Plasma and urine collected from 0-24 hours.

1 day

1 visit (in-person)

Washout Period

A washout period of at least 7 days between treatment arms to prevent drug interaction effects.

7 days

Treatment - Arm 2A: Furosemide Alone

Administration of a single dose of furosemide (5 mg) by mouth. Plasma and urine collected from 0-24 hours.

1 day

1 visit (in-person)

Washout Period

A washout period of at least 7 days between treatment arms to prevent drug interaction effects.

7 days

Treatment - Arm 2B: Furosemide + Probenecid

Administration of probenecid (1,000 mg) followed by furosemide (5 mg). Plasma and urine collected from 0-24 hours.

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

2-4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cimetidine
• Furosemide
• MetFORMIN
• Probenecid

Trial Overview The trial tests how well a biomarker panel can track kidney transporter activity using Metformin and Furosemide as probes for transporters OCTs/OATs. Cimetidine and Probenecid will be used to inhibit these transporters. The goal is to validate this method for future pediatric studies.

How Is the Trial Designed?

Group I: Arm 2B: furosemide + probenecid Experimental Treatment 2 Interventions

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 II: Arm 2A: furosemide alone (baseline) Experimental Treatment 1 Intervention

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 III: Arm 1B: metformin + cimetidine Experimental Treatment 2 Interventions

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 IV: Arm 1A: metformin alone (baseline) Experimental Treatment 1 Intervention

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.

Cimetidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Tagamet for:

• Gastroesophageal reflux disease (GERD)
• Peptic ulcer disease
• Zollinger-Ellison syndrome

Approved in United States as Tagamet for:

• Gastroesophageal reflux disease (GERD)
• Peptic ulcer disease
• Zollinger-Ellison syndrome
• Pathological hypersecretory conditions

Approved in Canada as Tagamet for:

• Gastroesophageal reflux disease (GERD)
• Peptic ulcer disease
• Zollinger-Ellison syndrome

Approved in Japan as Tagamet for:

• Gastroesophageal reflux disease (GERD)
• Peptic ulcer disease
• Zollinger-Ellison syndrome

Who Is Running the Clinical Trial?

Washington State University

Lead Sponsor

Trials

114

Recruited

58,800+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Published Research Related to This Trial

Cimetidine, an antiulcer medication, significantly inhibits liver enzymes that can alter the metabolism of various drugs, including warfarin and theophylline, which may lead to clinically important drug interactions.

Cimetidine can also raise gastric pH and affect liver blood flow, potentially exacerbating the effects of other medications, such as increasing the myelosuppressive effects of nitrosoureas and altering the absorption of ketoconazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cimetidine drug interactions. Greene, WL., Self, TH., Levinson, MJ.[2013]

In a study involving 12 healthy adults, cimetidine did not alter the absorption of temafloxacin, meaning it didn't affect how quickly or how much of the drug entered the bloodstream.

However, cimetidine reduced the clearance of temafloxacin by 19%, leading to a longer elimination half-life, but this interaction is not considered clinically significant due to the absence of serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cimetidine on the pharmacokinetics of temafloxacin. Sörgel, F., Granneman, GR., Stephan, U., et al.[2018]

Cimetidine is a strong inhibitor of liver microsomal activity, which can lead to significant drug interactions, particularly affecting the metabolism and excretion of medications like warfarin and propranolol, necessitating careful monitoring during combination therapy.

While cimetidine can enhance the absorption of certain drugs like pancreatic enzyme supplements, it may decrease the absorption of others, such as ketoconazole and elemental iron, highlighting the need for clinicians to be aware of these complex interactions in patient treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug interactions involving cimetidine--mechanisms, documentation, implications. Greene, W.[2019]

In a study involving 7 healthy subjects, cimetidine did not affect the metabolism or clearance of tolbutamide, indicating no significant pharmacokinetic interaction between the two drugs.

The total recovery of tolbutamide metabolites in urine was slightly lower when cimetidine was taken alongside tolbutamide, suggesting that cimetidine selectively inhibits certain drug oxidation processes without impacting tolbutamide's overall disposition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of inhibition of tolbutamide hydroxylation by cimetidine in man. Stockley, C., Keal, J., Rolan, P., et al.[2019]

Cimetidine, after five years of extensive use, has been associated with significant drug interactions, particularly with medications like warfarin and phenytoin, which can lead to adverse clinical effects.

Understanding the mechanisms behind these interactions, such as inhibition of drug metabolism and altered drug distribution, can help healthcare providers minimize the risk of further interactions when prescribing cimetidine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction of cimetidine with other drugs. Feely, J.[2019]

Lumacaftor and the metabolite ivacaftor-M6 significantly induce the activity of the enzyme CYP3A4, which could lead to reduced concentrations of ivacaftor in the body, potentially limiting its effectiveness.

While ivacaftor itself also induces CYP3A4, its other major metabolite (M1) and the new CFTR modulator tezacaftor do not show this effect, suggesting a complex interaction that may impact treatment outcomes for cystic fibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytochrome P450 3A4 Induction: Lumacaftor versus Ivacaftor Potentially Resulting in Significantly Reduced Plasma Concentration of Ivacaftor. Schneider, EK.[2020]

Antacids and adsorbents are generally considered safe and free from adverse effects, but they can interact with certain primary medications, potentially reducing their effectiveness.

The most significant interactions occur with drugs like ferrous sulfate, isoniazid, and tetracycline, which have strong evidence of clinical importance, while many reported interactions in the literature are overstated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-antacid interactions: assessment of clinical importance. D'Arcy, PF., McElnay, JC.[2019]

Patients with chronic disorders or those taking multiple medications are at a higher risk for drug interactions, which can lead to treatment failures and adverse reactions.

Drug interactions can occur through various mechanisms, including absorption issues, protein binding displacement, metabolism variability via the cytochrome P450 system, and renal excretion problems, highlighting the importance of monitoring drug levels, especially for medications with a narrow safety margin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug interactions: keeping it straight. Anastasio, GD., Cornell, KO., Menscer, D.[2005]

In a study involving 8 healthy volunteers, cimetidine did not affect the pharmacokinetics of single doses of femoxetine, but it significantly increased the plasma concentration of femoxetine after multiple doses.

Due to the increased levels of femoxetine when taken with cimetidine, it is recommended to reduce the femoxetine dose to 400 mg to ensure safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Femoxetine and cimetidine: interaction in healthy volunteers. Schmidt, J., Sørensen, AS., Gjerris, A., et al.[2019]

Citations

1. withpower.com withpower.com/trial/early-phase-1-interactions-3-2022-791d9

Combination Drugs for Drug Interactions · Info for Participants What data supports the effectiveness of the drug combination involving Cimetidine, Tagamet, Furosemide ... Probenecid, Benemid, Probecid? The research ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11309551/

Furosemide-probenecid Interaction as a Laboratory ... The data suggest that the exercise of the drug interaction between furosemide and probenecid is easy to perform, reproducible, and safe.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7688195/

Physiologically Based Pharmacokinetic Models of ... Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

4. go.drugbank.com go.drugbank.com/drugs/DB00695

Furosemide: Uses, Interactions, Mechanism of Action The risk or severity of adverse effects can be increased when Probenecid is combined with Furosemide. Procainamide, Furosemide may decrease the excretion ...

5. researchgate.net researchgate.net/publication/12024181_Furosemide-probenecid_interaction_as_a_laboratory_exercise_for_undergraduate_education_in_clinical_pharmacology

(PDF) Furosemide-probenecid interaction as a laboratory ... The data suggest that the exercise of the drug interaction between furosemide and probenecid is easy to perform, reproducible, and safe. Through ...

6. drugs.com drugs.com/drug-interactions/probenecid.html

Probenecid Interactions Checker There are 183 drugs known to interact with probenecid, along with 5 disease interactions. Of the total drug interactions, 7 are major, 76 are moderate, and 100 ...

7. mayoclinic.org mayoclinic.org/drugs-supplements/probenecid-oral-route/description/drg-20065625

Probenecid (oral route) - Side effects & dosage Probenecid is used in the treatment of chronic gout or gouty arthritis. These conditions are caused by too much uric acid in the blood.

8. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/abs/10.1067/mcp.2001.114671

Furosemide‐probenecid interaction as a laboratory exercise ... The data suggest that the exercise of the drug interaction between furosemide and probenecid is easy to perform, reproducible, and safe.