Flucloxacillin as an Inducer of CYP-enzymes

• Sponsor: University of Southern Denmark (Other)
• Overall Status: Completed
• CT.gov ID: NCT04840641
• Collaborator: SignaTope GmbH, Germany (Other)
• Enrollment: 14
• Location: 1
• Arms: 2
• Actual Duration (Months): 9.1
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers; Drug Drug Interaction	Drug: Flucloxacillin	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Flucloxacillin as an Inducer of CYP-enzymes
• Actual Study Start Date: Mar 25, 2021
• Actual Primary Completion Date: Dec 17, 2021
• Actual Study Completion Date: Dec 28, 2021

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Baseline The investigators measure the baseline of flucloxacillin and cocktaildrugs.
Experimental: Flucloxacillin treatment The investigators measure the concentration of flucloxacillin after 9 and 27 days and the concentration of cocktaildrugs after 10 and 28 days.	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; Other Names: Caffeine Efavirenz Losartan Omeprazole Metoprolol Midazolam

Outcome Measures

Primary Outcome Measures

1. 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

1. Change in AUC of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

2. Change in AUC of the metabolite of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

3. Change in Peak Plasma concentration (Cmax) of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

4. Change in Cmax of the metabolite of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

5. Change in Time to reach Cmax (Tmax) of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

6. Change in Tmax of the metabolite of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

7. Change in Renal Clearence (CLr) of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

8. Change in CLr of the metabolite of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

9. Change in Elimination half-life (T1/2) of midazolam [Day 10 and 28]

   Change in the activity of the drug metabolizing enzyme CYP3A4

10. Change in T1/2 of the metabolite of midazolam [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP3A4

11. Change in AUC of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

12. Change in AUC of the metabolite of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

13. Change in Cmax of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

14. Change in Cmax of the metabolite of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

15. Change in Tmax of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

16. Change in Tmax of the metabolite of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

17. Change in CLr of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

18. Change in CLr of the metabolite of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

19. Change in T1/2 of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

20. Change in T1/2 of the metabolite of metoprolol [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2D6

21. Change in AUC of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

22. Change in AUC of the metabolite of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

23. Change in Cmax of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

24. Change in Cmax of the metabolite of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

25. Change in Tmax of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

26. Change in Tmax of the metabolite of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

27. Change in CLr of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

28. Change in CLr of the metabolite of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

29. Change in T1/2 of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

30. Change in T1/2 of the metabolite of omeprazole [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C19

31. Change in AUC of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

32. Change in AUC of the metabolite of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

33. Change in Cmax of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

34. Change in Cmax of the metabolite of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

35. Change in Tmax of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

36. Change in Tmax of the metabolite of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

37. Change in CLr of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

38. Change in CLr of the metabolite of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

39. Change in T1/2 of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

40. Change in T1/2 of the metabolite of losartan [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2C9

41. Change in AUC of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

42. Change in AUC of the metabolite of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

43. Change in Cmax of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

44. Change in Cmax of the metabolite of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

45. Change in Tmax of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

46. Change in Tmax of the metabolite of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

47. Change in CLr of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

48. Change in CLr of the metabolite of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

49. Change in T1/2 of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

50. Change in T1/2 of the metabolite of efavirenz [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP2B6

51. Change in AUC of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

52. Change in AUC of the metabolite of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

53. Change in Cmax of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

54. Change in Cmax of the metabolite of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

55. Change in Tmax of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

56. Change in Tmax of the metabolite of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

57. Change in CLr of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

58. Change in CLr of the metabolite of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

59. Change in T1/2 of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

60. Change in T1/2 of the metabolite of caffeine [Day 10 and 28]

    Change in the activity of the drug metabolizing enzyme CYP1A2

61. Change in AUC of flucloxacillin [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 [Day 9 and 27]

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

63. Change in Cmax of flucloxacillin [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 [Day 9 and 27]

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

65. Change in Tmax of flucloxacillin [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 [Day 9 and 27]

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

67. Change in CLr of flucloxacillin [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 [Day 9 and 27]

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

69. Change in T1/2 of flucloxacillin [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 [Day 9 and 27]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Southern Denmark	Odense	Region Of Southern Denmark	Denmark	5000

Sponsors and Collaborators

• University of Southern Denmark
• SignaTope GmbH, Germany

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Southern Denmark
• ClinicalTrials.gov Identifier: NCT04840641
• Other Study ID Numbers: AKF-396; 2020-004044-28
• First Posted: Apr 12, 2021
• Last Update Posted: Jan 11, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Southern Denmark: CYP enzymes; Induction of CYP enzymes
• Additional relevant MeSH terms: Efavirenz; Floxacillin; Losartan; Metoprolol; Midazolam; Caffeine; Omeprazole

Study Results

No Results Posted as of Jan 11, 2022