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

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

Interventions

DRUG

Caffeine Tablet

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

DRUG

Bupropion Hydrochloride Capsels

1 x 20 mg tablet.

DRUG

Repaglinide Capsels

1 x 0,05 mg tablet.

DRUG

Flurbiprofen Capsels

1 x 10 mg tablet.

DRUG

Omeprazole 10 MG

1 x 10 mg tablet.

DRUG

Dextromethorphan Oral Solution

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

DRUG

Midazolam oral solution

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

DRUG

Simvastatin tablets

1 x 10 mg tablet.

DRUG

Placebo

2 x placebo tablets in the Placebo Phase/Arm

DRUG

Carvedilol

2 x 25 mg tablets

DRUG

Diclofenac

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

Sponsors & Collaborators

• University of Helsinki

  collaborator OTHER

• Helsinki University Central Hospital

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

CROSSOVER

Eligibility

Min Age

18 Years

Max Age

40 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-08-22

Primary Completion

2025-01-10

Completion

2025-01-10

Countries

• Finland

Study Locations