Clinical trial NCT04840641: Flucloxacillin as an Inducer of CYP-enzymes
Official title: Flucloxacillin as an Inducer of CYP-enzymes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Drug Drug Interaction
Keywords: CYP enzymes
Induction of CYP enzymes
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
Collaborators: name: SignaTope GmbH, Germany
First posted: 2021-04-12
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Change in Area under curve (AUC) of midazolam
timeFrame: Baseline and day 28
Secondary outcomes:
measure: Change in AUC of midazolam
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of midazolam
timeFrame: Day 10 and 28
measure: Change in Peak Plasma concentration (Cmax) of midazolam
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of midazolam
timeFrame: Day 10 and 28
measure: Change in Time to reach Cmax (Tmax) of midazolam
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of midazolam
timeFrame: Day 10 and 28
measure: Change in Renal Clearence (CLr) of midazolam
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of midazolam
timeFrame: Day 10 and 28
measure: Change in Elimination half-life (T1/2) of midazolam
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of midazolam
timeFrame: Day 10 and 28
measure: Change in AUC of metoprolol
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of metoprolol
timeFrame: Day 10 and 28
measure: Change in Cmax of metoprolol
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of metoprolol
timeFrame: Day 10 and 28
measure: Change in Tmax of metoprolol
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of metoprolol
timeFrame: Day 10 and 28
measure: Change in CLr of metoprolol
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of metoprolol
timeFrame: Day 10 and 28
measure: Change in T1/2 of metoprolol
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of metoprolol
timeFrame: Day 10 and 28
measure: Change in AUC of omeprazole
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of omeprazole
timeFrame: Day 10 and 28
measure: Change in Cmax of omeprazole
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of omeprazole
timeFrame: Day 10 and 28
measure: Change in Tmax of omeprazole
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of omeprazole
timeFrame: Day 10 and 28
measure: Change in CLr of omeprazole
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of omeprazole
timeFrame: Day 10 and 28
measure: Change in T1/2 of omeprazole
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of omeprazole
timeFrame: Day 10 and 28
measure: Change in AUC of losartan
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of losartan
timeFrame: Day 10 and 28
measure: Change in Cmax of losartan
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of losartan
timeFrame: Day 10 and 28
measure: Change in Tmax of losartan
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of losartan
timeFrame: Day 10 and 28
measure: Change in CLr of losartan
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of losartan
timeFrame: Day 10 and 28
measure: Change in T1/2 of losartan
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of losartan
timeFrame: Day 10 and 28
measure: Change in AUC of efavirenz
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of efavirenz
timeFrame: Day 10 and 28
measure: Change in Cmax of efavirenz
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of efavirenz
timeFrame: Day 10 and 28
measure: Change in Tmax of efavirenz
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of efavirenz
timeFrame: Day 10 and 28
measure: Change in CLr of efavirenz
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of efavirenz
timeFrame: Day 10 and 28
measure: Change in T1/2 of efavirenz
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of efavirenz
timeFrame: Day 10 and 28
measure: Change in AUC of caffeine
timeFrame: Day 10 and 28
measure: Change in AUC of the metabolite of caffeine
timeFrame: Day 10 and 28
measure: Change in Cmax of caffeine
timeFrame: Day 10 and 28
measure: Change in Cmax of the metabolite of caffeine
timeFrame: Day 10 and 28
measure: Change in Tmax of caffeine
timeFrame: Day 10 and 28
measure: Change in Tmax of the metabolite of caffeine
timeFrame: Day 10 and 28
measure: Change in CLr of caffeine
timeFrame: Day 10 and 28
measure: Change in CLr of the metabolite of caffeine
timeFrame: Day 10 and 28
measure: Change in T1/2 of caffeine
timeFrame: Day 10 and 28
measure: Change in T1/2 of the metabolite of caffeine
timeFrame: Day 10 and 28
measure: Change in AUC of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in AUC of the metabolite of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in Cmax of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in Cmax of the metabolite of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in Tmax of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in Tmax of the metabolite of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in CLr of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in CLr of the metabolite of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in T1/2 of flucloxacillin
timeFrame: Day 9 and 27
measure: Change in T1/2 of the metabolite of flucloxacillin
timeFrame: Day 9 and 27
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: University of Southern Denmark
state: Region Of Southern Denmark
Study officials:
References: