1. The Tale of Dicloxacillin To the Petri dish and back again Anton Pottegård Associate professor, Clinical Pharmacology and Pharmacy, University of Southern Denmark Head of Research, Hospital Pharmacy Funen, Odense University Hospital Chair, Danish Society for Pharmacoepidemiology Tore B. Stage Assistant professor, Clinical Pharmacology and Pharmacy, University of Southern Denmark
Danish Society of Pharmacology, 17/

4. Trombobasedata

6. Drug
Relative risk
Penicillin
1.68
ACE-inhibitors
1.28
Morphine
2.45
Oxycodon
1.85
Furosemide
1.42
Inhaled beta-agonist
1.57

7. Opgivende:
Virkelig dygtige medforfattere
Godt datamateriale
Sofistikeret metode
Konklusionen i paperet: Vi gjorde vores bedste, men det virkede ikke (ros fra Whitaker)
Screening er svært – men havde forventet mere

8. ?
FAILURE = PRE-SUCCES

14. Pottegård et al. JAMA 2015 Jul 21;314(3):296-7

15. Pottegård et al. JAMA 2015 Jul 21;314(3):296-7

16. Proton Pump Inhibitors
Dicloxacillin
Pottegård et al.
JAMA Jul 21;314(3):296-7.
Proton Pump Inhibitors
Henriksen et al.
Pharmacoepidemiol Drug Saf
2015 Dec;24(12):
Antidiabetics
Stage et al. J Thromb Haemost Jan; 14(1):129-33
Topical antimycotics
Hellfritzsch et al. Basic Clin Pharmacol Toxicol 2017 Apr;120(4):

17. Translational approach

18. Mechanism
CYP2C9

19. Sandwich-cultured hepatocytes

20. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
P450 activity
Cssmin, cssavg and cssmax
PXR activations data
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

21. Nuclear receptor activation
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

22. Dicloxacillin
Increased activity
Increased drug metabolism

23. Translational approach

24. Pharmacokinetic cocktail study

25. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP2C9
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

26. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP2C9
AUC GMR: 0.73 [ ]
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

27. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP2C19
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

28. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP2C19
AUC GMR: 0.33 [ ]
70% reduction in AUC
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

29. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP3A4
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

30. Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):510-519
CYP3A4
AUC GMR: 0.54 [ ]
Stage et al. Br J Clin Pharmacol 2018 Mar;84(3):

31. Too long didn’t read: Dicloxacillin induces Underlying mechanism:
CYP2C9
CYP2C19
CYP3A4
Underlying mechanism:
Dicloxacillin activates PXR 
↑ P450 expression and activity 
↑ Drug metabolism 
↓ Plasma concentrations and efficacy

37. Biases: Inserts warning against interaction / No intercourse (perhaps in particular during infection)
Rifampicin only ovulation in 11 of 21 users

41. Hellfritzsch et al. Unpublished data
Dicloxicilin
Penicilin
All
(n=47,248)
(n=47,258)
Male
29,868 (63.2%)
30,033 (63.6%)
Age (years)
Age, median (IQR)
75 (67-82)
75 (68-81)
18-69
14,615 (30.9%)
14,716 (31.1%)
70-79
16,972 (35.9%)
17,268 (36.5%)
80+
15,661 (33.1%)
15,274 (32.3%)
Indication for VKA
Atrial fibrillation/flutter
44,045 (93.2%)
44,034 (93.2%)
Mechanical heart valve
5,446 (11.5%)
5,450 (11.5%)
Hellfritzsch et al. Unpublished data

42. Hellfritzsch et al. Unpublished data
exposed
compare
exporate
comprate HR
All
107 of 47248
63 of 47258
2.3/1000
1.3/1000
1.72 ( )
Sex
Male
61 of 29868
29 of 30033
2.0/1000
1.0/1000
2.08 ( )
Female
46 of 17380
34 of 17225
2.6/1000
1.40 ( )
Age
<70 y
30 of 14615
19 of 14716
2.1/1000
1.57 ( )
70-79 y
30 of 16972
16 of 17268
1.8/1000
0.9/1000
1.85 ( )
80+ y
47 of 15661
28 of 15274
3.0/1000
1.72 ( )
Case-crossover 1.84
Hellfritzsch et al. Unpublished data

43. Hellfritzsch et al. Unpublished data
exposed
compare
exporate
comprate HR
All
104 of 45574
50 of 45581
2.3/1000
1.1/1000
2.14 ( )
Sex
Male
59 of 28769
30 of 28969
2.1/1000
1.0/1000
2.02 ( )
Female
45 of 16805
20 of 16612
2.7/1000
1.2/1000
2.31 ( )
Age
<70 y
30 of 14042
10 of 13847
0.7/1000
2.77 ( )
70-79 y
29 of 16203
19 of 17434
1.8/1000
1.78 ( )
80+ y
45 of 15329
21 of 14300
2.9/1000
1.5/1000
2.07 ( )
Hellfritzsch et al. Unpublished data

44. The end…?