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

32 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

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.

What data supports the effectiveness of the drug combination involving Cimetidine, Tagamet, Furosemide, Lasix, MetFORMIN, Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet, Probenecid, Benemid, Probecid?

The research highlights that Cimetidine, a component of the drug combination, is known for its interactions with other drugs due to its effect on liver enzymes, which can alter the metabolism and excretion of various medications. This suggests that careful monitoring is needed when using Cimetidine in combination with other drugs to ensure effectiveness and safety. ^{1 2 3 4 5}

Is the combination of drugs including Cimetidine generally safe for humans?

Cimetidine has been widely used for years, but it can interact with many other drugs, potentially causing adverse effects. It's important to monitor for interactions, especially if taking multiple medications, as Cimetidine can affect how other drugs are absorbed and eliminated in the body. ^{2 4 6 7 8}

What makes this drug combination unique for treating drug interactions?

This drug combination is unique because it includes cimetidine, which is known to interact with many drugs by inhibiting liver enzymes and affecting drug metabolism and excretion, potentially altering the effects of other drugs in the combination. ^{2 3 4 5 9}

Eligibility Criteria

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 from 18-65 years old and healthy

Exclusion Criteria

Are under 18 or over 65 years old

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.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Drug-antacid interactions: assessment of clinical importance. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Drug interactions: keeping it straight. [2005]

3. United States pubmed.ncbi.nlm.nih.gov

Cimetidine drug interactions. [2013]

4. England pubmed.ncbi.nlm.nih.gov

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

5. Germany pubmed.ncbi.nlm.nih.gov

Femoxetine and cimetidine: interaction in healthy volunteers. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Lack of inhibition of tolbutamide hydroxylation by cimetidine in man. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Interaction of cimetidine with other drugs. [2019]

8. United Arab Emirates pubmed.ncbi.nlm.nih.gov

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

9. Switzerland pubmed.ncbi.nlm.nih.gov

Effect of cimetidine on the pharmacokinetics of temafloxacin. [2018]