Flucloxacillin as an Inducer of CYP-enzymes

Study Overview
=================
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.

Official Title
-----------------
Flucloxacillin as an Inducer of CYP-enzymes

Conditions
-----------------
Healthy Volunteers, Drug Drug Interaction

Intervention / Treatment
-----------------
* Drug: Flucloxacillin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Baseline<br>The investigators measure the baseline of flucloxacillin and cocktaildrugs. | |
| Experimental: Flucloxacillin treatment<br>The investigators measure the concentration of flucloxacillin after 9 and 27 days and the concentration of cocktaildrugs after 10 and 28 days. | Drug: Flucloxacillin<br>* 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<br>* Other names: Midazolam;|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CYP enzymes, Induction of CYP enzymes