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Completed

NCT Number: NCT04840641

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.

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Key information

Conditions

Healthy Volunteers Drug Drug Interaction

Age range

18 year–55 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

University of Southern Denmark

Odense, Region Syddanmark, 5000, Denmark

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Flucloxacillin

Drug

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: Caffeine, Efavirenz, Losartan, Omeprazole, Metoprolol, Midazolam

Primary outcomes

  1. Change in Area under curve (AUC) of midazolam

    Time frame: Baseline and day 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

Secondary outcomes

  1. Change in AUC of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  2. Change in AUC of the metabolite of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  3. Change in Peak Plasma concentration (Cmax) of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  4. Change in Cmax of the metabolite of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  5. Change in Time to reach Cmax (Tmax) of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  6. Change in Tmax of the metabolite of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  7. Change in Renal Clearence (CLr) of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  8. Change in CLr of the metabolite of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  9. Change in Elimination half-life (T1/2) of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  10. Change in T1/2 of the metabolite of midazolam

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP3A4

  11. Change in AUC of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  12. Change in AUC of the metabolite of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  13. Change in Cmax of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  14. Change in Cmax of the metabolite of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  15. Change in Tmax of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  16. Change in Tmax of the metabolite of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  17. Change in CLr of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  18. Change in CLr of the metabolite of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  19. Change in T1/2 of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  20. Change in T1/2 of the metabolite of metoprolol

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2D6

  21. Change in AUC of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  22. Change in AUC of the metabolite of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  23. Change in Cmax of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  24. Change in Cmax of the metabolite of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  25. Change in Tmax of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  26. Change in Tmax of the metabolite of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  27. Change in CLr of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  28. Change in CLr of the metabolite of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  29. Change in T1/2 of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  30. Change in T1/2 of the metabolite of omeprazole

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C19

  31. Change in AUC of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  32. Change in AUC of the metabolite of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  33. Change in Cmax of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  34. Change in Cmax of the metabolite of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  35. Change in Tmax of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  36. Change in Tmax of the metabolite of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  37. Change in CLr of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  38. Change in CLr of the metabolite of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  39. Change in T1/2 of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  40. Change in T1/2 of the metabolite of losartan

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2C9

  41. Change in AUC of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  42. Change in AUC of the metabolite of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  43. Change in Cmax of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  44. Change in Cmax of the metabolite of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  45. Change in Tmax of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  46. Change in Tmax of the metabolite of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  47. Change in CLr of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  48. Change in CLr of the metabolite of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  49. Change in T1/2 of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  50. Change in T1/2 of the metabolite of efavirenz

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP2B6

  51. Change in AUC of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  52. Change in AUC of the metabolite of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  53. Change in Cmax of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  54. Change in Cmax of the metabolite of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  55. Change in Tmax of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  56. Change in Tmax of the metabolite of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  57. Change in CLr of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  58. Change in CLr of the metabolite of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  59. Change in T1/2 of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  60. Change in T1/2 of the metabolite of caffeine

    Time frame: Day 10 and 28

    Change in the activity of the drug metabolizing enzyme CYP1A2

  61. Change in AUC of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  62. Change in AUC of the metabolite of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  63. Change in Cmax of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  64. Change in Cmax of the metabolite of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  65. Change in Tmax of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  66. Change in Tmax of the metabolite of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  67. Change in CLr of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  68. Change in CLr of the metabolite of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  69. Change in T1/2 of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

  70. Change in T1/2 of the metabolite of flucloxacillin

    Time frame: Day 9 and 27

    Change in the activity of the enzyme responsible for metabolism of flucloxacillin

Sponsors and collaborators

Lead sponsor

University of Southern Denmark

Other

Collaborators

  • SignaTope GmbH, Germany

Registry information

Important dates

Study start
2021
Primary completion
2021
Study completion
2021
First posted
Apr 12, 2021
Registry last updated
Jan 11, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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