Flucloxacillin as an Inducer of CYP-enzymes

Healthy Volunteers Clinical Trial

Official title:

Flucloxacillin as an Inducer of CYP-enzymes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04840641
• Other study ID #: AKF-396
• Secondary ID: 2020-004044-28
• Status: Completed
• Phase: Phase 1
• Start date: March 25, 2021
• Est. completion date: December 28, 2021

Study information

• Verified date: January 2022
• Source: University of Southern Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: December 28, 2021
• Est. primary completion date: December 17, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Drug Drug Interaction
• Healthy Volunteers

Intervention

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

Locations

Country	Name	City	State
Denmark	University of Southern Denmark	Odense	Region Of Southern Denmark

Sponsors (2)

Lead Sponsor	Collaborator
University of Southern Denmark	SignaTope GmbH, Germany

Country where clinical trial is conducted

Denmark, 

Outcome

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