Flucloxacillin as an Inducer of CYP-enzymes
- Registration Number
- NCT04840641
- Lead Sponsor
- University of Southern Denmark
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 14
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Flucloxacillin treatment Flucloxacillin The investigators measure the concentration of flucloxacillin after 9 and 27 days and the concentration of cocktaildrugs after 10 and 28 days.
- Primary Outcome Measures
Name Time Method Change in Area under curve (AUC) of midazolam Baseline and day 28 Change in the activity of the drug metabolizing enzyme CYP3A4
- Secondary Outcome Measures
Name Time Method Change in Cmax of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in Cmax of the metabolite of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in Tmax of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in Tmax of the metabolite of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in CLr of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in CLr of the metabolite of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in T1/2 of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in T1/2 of the metabolite of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in AUC of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in AUC of the metabolite of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in Cmax of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in Cmax of the metabolite of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in Tmax of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in Tmax of the metabolite of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in CLr of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in AUC of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in AUC of the metabolite of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Peak Plasma concentration (Cmax) of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Cmax of the metabolite of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Time to reach Cmax (Tmax) of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Tmax of the metabolite of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Renal Clearence (CLr) of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in CLr of the metabolite of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Elimination half-life (T1/2) of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in Cmax of the metabolite of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in Tmax of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in Tmax of the metabolite of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in CLr of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in CLr of the metabolite of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in T1/2 of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in T1/2 of the metabolite of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in AUC of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in AUC of the metabolite of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in Cmax of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in Cmax of the metabolite of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in Tmax of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in Tmax of the metabolite of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in T1/2 of the metabolite of midazolam Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP3A4
Change in AUC of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in AUC of the metabolite of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in Cmax of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in Cmax of the metabolite of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in Tmax of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in Tmax of the metabolite of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in CLr of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in CLr of the metabolite of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in T1/2 of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in T1/2 of the metabolite of metoprolol Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2D6
Change in AUC of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in AUC of the metabolite of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in Cmax of omeprazole Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C19
Change in CLr of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in CLr of the metabolite of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in T1/2 of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in T1/2 of the metabolite of losartan Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2C9
Change in AUC of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in AUC of the metabolite of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in Cmax of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in Cmax of the metabolite of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in Tmax of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in Tmax of the metabolite of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in CLr of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in CLr of the metabolite of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in T1/2 of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in T1/2 of the metabolite of efavirenz Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP2B6
Change in AUC of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in AUC of the metabolite of caffeine Day 10 and 28 Change in the activity of the drug metabolizing enzyme CYP1A2
Change in CLr of the metabolite of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in T1/2 of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Change in T1/2 of the metabolite of flucloxacillin Day 9 and 27 Change in the activity of the enzyme responsible for metabolism of flucloxacillin
Trial Locations
- Locations (1)
University of Southern Denmark
🇩🇰Odense, Region Of Southern Denmark, Denmark
University of Southern Denmark🇩🇰Odense, Region Of Southern Denmark, Denmark