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

KF2022#4-tutkimus:Beetasalpaajan ja tulehduskipulääkkeen Vaikutus CYP-entsyymivälitteiseen lääkeainemetaboliaan

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.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: 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; Drug: Carvedilol; Drug: Diclofenac

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland
    • Department of Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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; 0,5 x 100 mg tablet (50 mg caffeine).; Other Names: YA Kofeiinitabletti 100 mg, Yliopiston apteekki; Drug: Bupropion Hydrochloride Capsels; 1 x 20 mg tablet.; Other Names: Bupropion hydrochloride 20 mg caps, HUS Apteekki; Drug: Repaglinide Capsels; 1 x 0,05 mg tablet.; Other Names: Repaglinide 0.05 mg caps, HUS Apteekki; Drug: Flurbiprofen Capsels; 1 x 10 mg tablet.; Other Names: Flurbiprofen 10 mg caps, HUS Apteekki; Drug: Omeprazole 10 MG; 1 x 10 mg tablet.; Other Names: Losec Mups 10 mg enterotablet, AstraZeneca; Drug: Dextromethorphan Oral Solution; 5,0 ml of 2 mg/ml oral solution (10 mg dextromethorphan).; Other Names: Rometor Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Midazolam oral solution; 0,5 ml of 2 mg/ml oral solution (1,0 mg midazolam).; Other Names: Midazolam-Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Simvastatin tablets; 1 x 10 mg tablet.; Other Names: Simvastatin Krka 10 mg tablet, KRKA; Drug: Placebo; 2 x placebo tablets in the Placebo Phase/Arm; Other Names: Placebo, 9 mm tablet, Yliopiston apteekki
Active Comparator: Carvedilol; 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; 0,5 x 100 mg tablet (50 mg caffeine).; Other Names: YA Kofeiinitabletti 100 mg, Yliopiston apteekki; Drug: Bupropion Hydrochloride Capsels; 1 x 20 mg tablet.; Other Names: Bupropion hydrochloride 20 mg caps, HUS Apteekki; Drug: Repaglinide Capsels; 1 x 0,05 mg tablet.; Other Names: Repaglinide 0.05 mg caps, HUS Apteekki; Drug: Flurbiprofen Capsels; 1 x 10 mg tablet.; Other Names: Flurbiprofen 10 mg caps, HUS Apteekki; Drug: Omeprazole 10 MG; 1 x 10 mg tablet.; Other Names: Losec Mups 10 mg enterotablet, AstraZeneca; Drug: Dextromethorphan Oral Solution; 5,0 ml of 2 mg/ml oral solution (10 mg dextromethorphan).; Other Names: Rometor Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Midazolam oral solution; 0,5 ml of 2 mg/ml oral solution (1,0 mg midazolam).; Other Names: Midazolam-Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Simvastatin tablets; 1 x 10 mg tablet.; Other Names: Simvastatin Krka 10 mg tablet, KRKA; Drug: Carvedilol; 2 x 25 mg tablets; Other Names: Carvedilol STADA 25 mg tablet, STADA Arzneimittel AG
Active Comparator: Diclofenac; 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; 0,5 x 100 mg tablet (50 mg caffeine).; Other Names: YA Kofeiinitabletti 100 mg, Yliopiston apteekki; Drug: Bupropion Hydrochloride Capsels; 1 x 20 mg tablet.; Other Names: Bupropion hydrochloride 20 mg caps, HUS Apteekki; Drug: Repaglinide Capsels; 1 x 0,05 mg tablet.; Other Names: Repaglinide 0.05 mg caps, HUS Apteekki; Drug: Flurbiprofen Capsels; 1 x 10 mg tablet.; Other Names: Flurbiprofen 10 mg caps, HUS Apteekki; Drug: Omeprazole 10 MG; 1 x 10 mg tablet.; Other Names: Losec Mups 10 mg enterotablet, AstraZeneca; Drug: Dextromethorphan Oral Solution; 5,0 ml of 2 mg/ml oral solution (10 mg dextromethorphan).; Other Names: Rometor Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Midazolam oral solution; 0,5 ml of 2 mg/ml oral solution (1,0 mg midazolam).; Other Names: Midazolam-Ratiopharm 2 mg/ml oral solution, Ratiopharm; Drug: Simvastatin tablets; 1 x 10 mg tablet.; Other Names: Simvastatin Krka 10 mg tablet, KRKA; Drug: Diclofenac; 1 x 50 mg tablet (three times daily for three days); Other Names: Voltaren Rapid 50 mg, Novartis Finland Oy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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.

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Collaborators: University of Helsinki

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2024
• Primary Completion (Actual): January 10, 2025
• Study Completion (Actual): January 10, 2025

Study Registration Dates

• First Submitted: August 4, 2024
• First Submitted That Met QC Criteria: August 20, 2024
• First Posted (Actual): August 22, 2024

Study Record Updates

• Last Update Posted (Actual): March 6, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Dosage Forms; Hydrocarbons; Hydrocarbons, Cyclic; Acids, Acyclic; Carboxylic Acids; Alkaloids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Amines; Indoles; Purinones; Purines; Benzene Derivatives; Alcohols; Benzazepines; Heterocyclic Compounds, 4 or More Rings; Propanolamines; Amino Alcohols; Propanols; Acids, Carbocyclic; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Benzodiazepines; Heterocyclic Compounds, 3-Ring; Ketones; Propionates; Phenylacetates; Carbazoles; Biphenyl Compounds; Xanthines; Lovastatin; Propiophenones; Carvedilol; Midazolam; Caffeine; Omeprazole; Bupropion; Dextromethorphan; Diclofenac; Simvastatin; Flurbiprofen; Tablets; Solutions; Capsules; repaglinide
• Other Study ID Numbers: KF2022#4; 2023-000002-25 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No