KF2022#4-trial: Effects of a Beta Blocker and NSAID on CYP Mediated Drug Metabolism

NCT06566794 | Completed

• 2 other identifiers: KF2022#42023-000002-25
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Carvedilol is a non-selective beta-blocker in common clinical use, used to treat hypertension, heart failure, and angina pectoris symptoms associated with coronary artery disease. Diclofenac is a non-selective anti-inflammatory drug in general use, which is used to treat rheumatic diseases, osteoarthritis, musculoskeletal pain conditions, menstrual pains and migraines, among others. In our recent experiments involving liver cell enzymes, both carvedilol and diclofenac were found to inhibit several cytochrome P450 (CYP) enzymes central to drug metabolism, potentially leading to adverse drug interactions with other drugs metabolized by the same enzyme. The purpose of this study is to investigate the effects of the use of carvedilol and diclofenac on the activity of key CYP enzymes in drug metabolism in healthy volunteers using a low-dose model drug combination covering seven CYP enzymes. In an open three-phase, randomized, crossover study with 12 healthy volunteers, the subjects will receive a drug combination of caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam and simvastatin and as a premedication either placebo, carvedilol or diclofenac. Blood samples will be collected and carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam and simvastatin pharmacokinetics will be monitored up to 23 hours post dose.

Conditions

Drug Interaction

Outcome Measures

Primary Outcomes (1)

• Area under the plasma concentration - time curve of carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam and simvastatin

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

Secondary Outcomes (5)

• Peak plasma concentration for carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam, simvastatin and their metabolites.

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

• Half-life for carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam, simvastatin and their metabolites.

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

• Time to peak plasma concentration for carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam, simvastatin and their metabolites.

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

• Fractional areas under concentration-time curve (AUC) for carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam, simvastatin and their metabolites.

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

• Areas under concentration-time curve (AUC) for carvedilol, diclofenac, caffeine, bupropion, repaglinide, flurbiprofen, omeprazole, dextromethorphan, midazolam, simvastatin and their metabolites.

  Prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 23 hours after administration the drugs.

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Placebo tablets (2 x Placebo) and 150 ml water at 8.00 a.m. on the study day. Study drug doses (caffeine 50 mg, bupropion 20 mg, repaglinide 0,05 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1,0 mg, simvastatin 10 mg) and 250 ml water at 9:00 a.m.

Drug: Caffeine Tablet; Drug: Bupropion Hydrochloride Capsels; Drug: Repaglinide Capsels; Drug: Flurbiprofen Capsels; Drug: Omeprazole 10 MG; Drug: Dextromethorphan Oral Solution; Drug: Midazolam oral solution; Drug: Simvastatin tablets; Drug: Placebo

Carvedilol

ACTIVE COMPARATOR

Carvedilol tablets (2 x Carvedilol STADA 25 mg) and 150 ml water at 8.00 a.m. on the study day. Study drug doses (caffeine 50 mg, bupropion 20 mg, repaglinide 0,05 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1,0 mg, simvastatin 10 mg) and 250 ml water at 9:00 a.m.

Drug: Caffeine Tablet; Drug: Bupropion Hydrochloride Capsels; Drug: Repaglinide Capsels; Drug: Flurbiprofen Capsels; Drug: Omeprazole 10 MG; Drug: Dextromethorphan Oral Solution; Drug: Midazolam oral solution; Drug: Simvastatin tablets; Drug: Carvedilol

Diclofenac

ACTIVE COMPARATOR

Diclofenac tablet (1 x Voltaren Rapid 50 mg) three times a day around 8.00 a.m., 3.00 p.m. and 9.00 p.m. for three days. Diclofenac tablet (1 x Voltaren Rapid 50 mg) and 150 ml water at 8.00 a.m., 3.00 p.m. and 9.00 p.m. on the study day (3rd day of diclofenac treatment). Study drug doses (caffeine 50 mg, bupropion 20 mg, repaglinide 0,05 mg, flurbiprofen 10 mg, omeprazole 10 mg, dextromethorphan 10 mg, midazolam 1,0 mg, simvastatin 10 mg) and 250 ml water at 9:00 a.m.

Drug: Caffeine Tablet; Drug: Bupropion Hydrochloride Capsels; Drug: Repaglinide Capsels; Drug: Flurbiprofen Capsels; Drug: Omeprazole 10 MG; Drug: Dextromethorphan Oral Solution; Drug: Midazolam oral solution; Drug: Simvastatin tablets; Drug: Diclofenac

Interventions

Caffeine Tablet DRUG

0,5 x 100 mg tablet (50 mg caffeine).

Also known as: YA Kofeiinitabletti 100 mg, Yliopiston apteekki

Carvedilol; Diclofenac; Placebo

Bupropion Hydrochloride Capsels DRUG

1 x 20 mg tablet.

Also known as: Bupropion hydrochloride 20 mg caps, HUS Apteekki

Carvedilol; Diclofenac; Placebo

Repaglinide Capsels DRUG

1 x 0,05 mg tablet.

Also known as: Repaglinide 0.05 mg caps, HUS Apteekki

Carvedilol; Diclofenac; Placebo

Flurbiprofen Capsels DRUG

1 x 10 mg tablet.

Also known as: Flurbiprofen 10 mg caps, HUS Apteekki

Carvedilol; Diclofenac; Placebo

Omeprazole 10 MG DRUG

1 x 10 mg tablet.

Also known as: Losec Mups 10 mg enterotablet, AstraZeneca

Carvedilol; Diclofenac; Placebo

Dextromethorphan Oral Solution DRUG

5,0 ml of 2 mg/ml oral solution (10 mg dextromethorphan).

Also known as: Rometor Ratiopharm 2 mg/ml oral solution, Ratiopharm

Carvedilol; Diclofenac; Placebo

Midazolam oral solution DRUG

0,5 ml of 2 mg/ml oral solution (1,0 mg midazolam).

Also known as: Midazolam-Ratiopharm 2 mg/ml oral solution, Ratiopharm

Carvedilol; Diclofenac; Placebo

Simvastatin tablets DRUG

1 x 10 mg tablet.

Also known as: Simvastatin Krka 10 mg tablet, KRKA

Carvedilol; Diclofenac; Placebo

Placebo DRUG

2 x placebo tablets in the Placebo Phase/Arm

Also known as: Placebo, 9 mm tablet, Yliopiston apteekki

Placebo

Carvedilol DRUG

2 x 25 mg tablets

Also known as: Carvedilol STADA 25 mg tablet, STADA Arzneimittel AG

Carvedilol

Diclofenac DRUG

1 x 50 mg tablet (three times daily for three days)

Also known as: Voltaren Rapid 50 mg, Novartis Finland Oy

Diclofenac

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written informed consent
• Age 18-40
• Healthy
• Systolic blood pressure ≥110 mmHg
• Heart rate ≥ 55/min
• Normal ECG
• Accepted results from laboratory tests (blood haemoglobin, basic blood count and blood platelets, alanine aminotransferase, alkaline phosphatase, glutamyl transferase, creatine kinase, creatinine, plasma glucose concentration, plasma potassium and sodium). Negative pregnancy test result (serum human chorionic gonadotropin) for women.

You may not qualify if:

• Significant disease
• Previous or current gastrointestinal bleeding, ulcer or perforation
• Findings of a medical examination and laboratory tests, which require a more detailed examination of the state of health
• Smoking
• Hormonal birth control or other regular medication
• Pregnancy (current or planned) or nursing
• Participation in any other studies involving investigational or marketed drug products within three months prior to the entry into this study
• Donation of blood within three months prior to the entry into this study
• Significant overweight / small or hard-to-find veins
• BMI \< 18.5 kg/m2
• Insufficient Finnish language skills
• Hypersensitivity or contraindication to study drugs

Sponsors & Collaborators

• Helsinki University Central Hospital: lead
• University of Helsinki: collaborator

Study Sites (1)

Department of Clinical Pharmacology

Helsinki, Finland

Location

MeSH Terms

Interventions

Caffeine; Bupropion; Capsules; repaglinide; Flurbiprofen; Omeprazole; Dextromethorphan; Solutions; Midazolam; Simvastatin; Tablets; Carvedilol; Diclofenac

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Propiophenones; Ketones; Organic Chemicals; Dosage Forms; Pharmaceutical Preparations; Propionates; Acids, Acyclic; Carboxylic Acids; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Lovastatin; Naphthalenes; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 3-Ring; Phenylacetates; Acids, Carbocyclic

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Head physician

Study Record Dates

• First Submitted: August 4, 2024
• First Posted: August 22, 2024
• Study Start: August 22, 2024
• Primary Completion: January 10, 2025
• Study Completion: January 10, 2025
• Last Updated: March 6, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

FI (1)