Flucloxacillin as an Inducer of CYP-enzymes

NCT04840641 | Completed Phase 1

• 2 other identifiers: AKF-3962020-004044-28
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

Worldwide there is an increase in antibiotic resistance which may have potential fatal long-term consequences. This is due to extensive use and sometimes misuse of antibiotics in the treatment of harmless infections. The aim of this study is to investigate if treatment with flucloxacillin increases drug metabolism in healthy volunteers through induction of cytochrome P450 (CYP) enzymes, CYP1A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The hypothesis is based on an in vitro study showing that flucloxacillin activates a receptor (PXR) responsible for transcription of CYP enzymes. Trial subjects will ingest flucloxacillin for 31 days and at day 10 and 28 ingest a cocktail of 6 drugs to determine if the CYP enzymes have been induced. Plasma and urine will be drawn over 72 hours to determine the concentration of the 6 drugs and their metabolites. Change in flucloxacillin concentration will also be measured at day 9 and 27 to establish if flucloxacillin induces its own metabolism.

Conditions

Healthy Volunteers; Drug Drug Interaction

Keywords

CYP enzymes; Induction of CYP enzymes

Outcome Measures

Primary Outcomes (1)

• Change in Area under curve (AUC) of midazolam

  Change in the activity of the drug metabolizing enzyme CYP3A4

  Baseline and day 28

Secondary Outcomes (70)

• Change in AUC of midazolam

  Day 10 and 28

• Change in AUC of the metabolite of midazolam

  Day 10 and 28

• Change in Peak Plasma concentration (Cmax) of midazolam

  Day 10 and 28

• Change in Cmax of the metabolite of midazolam

  Day 10 and 28

• Change in Time to reach Cmax (Tmax) of midazolam

  Day 10 and 28

Study Arms (2)

Baseline

NO INTERVENTION

The investigators measure the baseline of flucloxacillin and cocktaildrugs.

Flucloxacillin treatment

EXPERIMENTAL

The investigators measure the concentration of flucloxacillin after 9 and 27 days and the concentration of cocktaildrugs after 10 and 28 days.

Drug: Flucloxacillin

Interventions

Flucloxacillin DRUG

Healthy volunteers will take 2x500 mg flucloxacillin 3 times a day for 31 days. The investigators will measure the baseline concentration of the 6-cocktaildrugs and flucloxacillin before start of 31 days of flucloxacillin treatment. On day 9 and 27 the investigators will measure the concentration of flucloxacillin. On day 10 and 28 the investigators will measure the concentration of the 6 cocktaildrugs

Also known as: Caffeine, Efavirenz, Losartan, Omeprazole, Metoprolol, Midazolam

Flucloxacillin treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-55 years
• The following data have to be in the normal range or only clinical insignificantly different from this: eGFR, ALAT, bilirubin, HbA1c, haemoglobin
• BMI 18.5 - 29.9 kg m-2
• Non-smoker (abstained from smoking minimum 2 weeks before the first study day and during the trial)
• Generally healthy
• Willing to give informed consent

You may not qualify if:

• Known sensitivity to any of the used drugs or any excipients listed in section 6.1 in the Summary of Product Characteristics (SmPC).
• Known allergy towards penicillin or cephalosporines
• Any of the following diseases (current or previous):
• Heart disease, known family history of prolonged QTc interval, sudden death or conditions that might prolonged QTc-intervals, hypotension, severe disturbance of electrolyte balance e.g. hypokalemia or hypomagnesemia, myasthenia gravis, lung- or respiratory diseases, an anatomically abnormality of the respiratory tract, sleep apnea syndrome
• \- Intake of any significant prescription drugs, over-the- counter drugs, herbal drugs or dietary supplements. Contraindicated drugs include: Benzodiazepines, beta blockers, ergot alkaloids, herbal preparations containing St. John's wort, antiarrhythmics, neuroleptics, antidepressive agents, antibiotics, antifungal agents, non-sedating antihistamines, antimalarials, methadone, elbasvir, grazoprevir, nelfinavir cisapride, pimozide, bepridil
• Alcohol abuse or if the Danish Health Authority recommendation regarding alcohol intake has been exceeded 2 weeks before the first study day (men 14 units alcohol/week, women 7 units alcohol/week)
• Women who are breastfeeding
• Participation in any other interventional trials

Sponsors & Collaborators

• University of Southern Denmark: lead
• SignaTope GmbH, Germany: collaborator

Study Sites (1)

University of Southern Denmark

Odense, Region Syddanmark, 5000, Denmark

Location

MeSH Terms

Interventions

Floxacillin; Caffeine; efavirenz; Losartan; Omeprazole; Metoprolol; Midazolam

Intervention Hierarchy (Ancestors)

Cloxacillin; Oxacillin; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Xanthines; Alkaloids; Purinones; Purines; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Tetrazoles; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Benzimidazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Benzodiazepines; Benzazepines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2021
• First Posted: April 12, 2021
• Study Start: March 25, 2021
• Primary Completion: December 17, 2021
• Study Completion: December 28, 2021
• Last Updated: January 11, 2022

Record last verified: 2022-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)