Flucloxacillin as an Inducer of CYP-enzymes

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers; Drug Drug Interaction
• Intervention / Treatment: Drug: Flucloxacillin

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Region Of Southern Denmark
    • Odense, Region Of Southern Denmark, Denmark, 5000
      • University of Southern Denmark

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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
• Positive pregnancy test at inclusion screening or at any of the study days
• Participation in any other interventional trials

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Baseline; The investigators measure the baseline of flucloxacillin and cocktaildrugs.
Experimental: Flucloxacillin treatment; The investigators measure the concentration of flucloxacillin after 9 and 27 days and the concentration of cocktaildrugs after 10 and 28 days.	Drug: Flucloxacillin; 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; Other Names: Losartan; Metoprolol; Midazolam; Omeprazole; Efavirenz; Caffeine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Area under curve (AUC) of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Baseline and day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in AUC of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in AUC of the metabolite of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Peak Plasma concentration (Cmax) of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Cmax of the metabolite of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Time to reach Cmax (Tmax) of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Tmax of the metabolite of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Renal Clearence (CLr) of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in CLr of the metabolite of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in Elimination half-life (T1/2) of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in T1/2 of the metabolite of midazolam	Change in the activity of the drug metabolizing enzyme CYP3A4	Day 10 and 28
Change in AUC of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in AUC of the metabolite of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in Cmax of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in Cmax of the metabolite of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in Tmax of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in Tmax of the metabolite of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in CLr of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in CLr of the metabolite of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in T1/2 of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in T1/2 of the metabolite of metoprolol	Change in the activity of the drug metabolizing enzyme CYP2D6	Day 10 and 28
Change in AUC of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in AUC of the metabolite of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in Cmax of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in Cmax of the metabolite of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in Tmax of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in Tmax of the metabolite of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in CLr of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in CLr of the metabolite of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in T1/2 of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in T1/2 of the metabolite of omeprazole	Change in the activity of the drug metabolizing enzyme CYP2C19	Day 10 and 28
Change in AUC of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in AUC of the metabolite of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in Cmax of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in Cmax of the metabolite of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in Tmax of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in Tmax of the metabolite of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in CLr of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in CLr of the metabolite of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in T1/2 of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in T1/2 of the metabolite of losartan	Change in the activity of the drug metabolizing enzyme CYP2C9	Day 10 and 28
Change in AUC of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in AUC of the metabolite of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in Cmax of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in Cmax of the metabolite of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in Tmax of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in Tmax of the metabolite of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in CLr of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in CLr of the metabolite of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in T1/2 of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in T1/2 of the metabolite of efavirenz	Change in the activity of the drug metabolizing enzyme CYP2B6	Day 10 and 28
Change in AUC of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in AUC of the metabolite of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in Cmax of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in Cmax of the metabolite of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in Tmax of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in Tmax of the metabolite of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in CLr of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in CLr of the metabolite of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in T1/2 of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in T1/2 of the metabolite of caffeine	Change in the activity of the drug metabolizing enzyme CYP1A2	Day 10 and 28
Change in AUC of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in AUC of the metabolite of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in Cmax of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in Cmax of the metabolite of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in Tmax of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in Tmax of the metabolite of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in CLr of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in CLr of the metabolite of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in T1/2 of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27
Change in T1/2 of the metabolite of flucloxacillin	Change in the activity of the enzyme responsible for metabolism of flucloxacillin	Day 9 and 27

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Collaborators: SignaTope GmbH, Germany

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2021
• Primary Completion (Actual): December 17, 2021
• Study Completion (Actual): December 28, 2021

Study Registration Dates

• First Submitted: March 23, 2021
• First Submitted That Met QC Criteria: April 8, 2021
• First Posted (Actual): April 12, 2021

Study Record Updates

• Last Update Posted (Actual): January 11, 2022
• Last Update Submitted That Met QC Criteria: January 10, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: CYP enzymes; Induction of CYP enzymes
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Anti-Ulcer Agents; Proton Pump Inhibitors; Cytochrome P-450 CYP3A Inducers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Cytochrome P-450 CYP2C19 Inhibitors; Midazolam; Losartan; Metoprolol; Caffeine; Omeprazole; Floxacillin; Efavirenz
• Other Study ID Numbers: AKF-396; 2020-004044-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual participant data cannot be shared due to general data protection regulation (GDPR).

Drug and device information, study documents

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