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

Helsinki University Central Hospital (HUCH)

Status: Not yet enrolling

Conditions: Drug Interaction

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

Study type: Interventional

Funder types: Other

Identifiers

NCT06566794

KF2022#4

2023-000002-25 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 12 estimated patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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12 participants in 3 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Flurbiprofen Capsels

Drug: Simvastatin tablets

Drug: Placebo

Drug: Dextromethorphan Oral Solution

Drug: Bupropion Hydrochloride Capsels

Drug: Repaglinide Capsels

Drug: Caffeine Tablet

Drug: Midazolam oral solution

Drug: Omeprazole 10 MG

Carvedilol

Active Comparator group

Description:

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.

Treatment:

Drug: Flurbiprofen Capsels

Drug: Simvastatin tablets

Drug: Dextromethorphan Oral Solution

Drug: Bupropion Hydrochloride Capsels

Drug: Carvedilol

Drug: Repaglinide Capsels

Drug: Caffeine Tablet

Drug: Midazolam oral solution

Drug: Omeprazole 10 MG

Diclofenac

Active Comparator group

Description:

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.

Treatment:

Drug: Flurbiprofen Capsels

Drug: Simvastatin tablets

Drug: Diclofenac

Drug: Dextromethorphan Oral Solution

Drug: Bupropion Hydrochloride Capsels

Drug: Repaglinide Capsels

Drug: Caffeine Tablet

Drug: Midazolam oral solution

Drug: Omeprazole 10 MG