Glucocoricoid replacement in pituitary disease. Are we getting this right? Karim Meeran 23 rd May 2018

Transcription

1 Glucocoricoid replacement in pituitary disease. Are we getting this right? Karim Meeran 23 rd May 2018

2 Cortisol has diurnal rhythm Life on earth has evolved in the presence of a rotating earth, with a period of 24 hours over millions of years. (3.7 billion years)

3 Cortisol has diurnal rhythm Life on earth has evolved in the presence of a rotating earth, with a period of 24 hours over millions of years. Humans thus have evolved an endogenous circadian rhythm to match time of day. Can we mimic this in patients who have no pituitary or Addisons?

4 Cortisol has diurnal rhythm (debono and Ross 2009) Peak at 8.32am 441nM 428nM 330nM Increase starts 5am 55nM 110nM 144nM

5

6

7 An evening dose of hydrocortisone is thus very potent, and as unhealthy as working shifts

8 MW 362 When given by mouth, has too short a half life to be given once daily.

9 Hydrocortisone On the WHO list of drugs needed in all healthcare systems as essential.

10 How much does hydrocortisone cost? One months supply at 20mg daily? 1 per month 15 per month 150 per month 1000 per month

11 BNF 2007

12 BNF 2010

13

14 BNF 2014

15 Hydrocortisone price increase Merck stopped making hydrocortisone, so it was then imported Then one company (Auden McKenzie) got a licence, and blocked importation of other brands (not sure how, but corrupt) Then they had a monopoly October per month

16

17 Smooth curve These peaks are thought to be harmful (as harmful as night shifts)

18 Smooth curve Which of the following is as harmful as a night shift? 10mg hydrocortisone at 7am 5mg hydrocortisone at 4pm

19 MW 362 When given by mouth, has too short a half life to be given once daily. We need to have a longer lasting version. One option is to have the rise before wakening: a DELAYED release

20 Chronocort

21 Chronocort at 10pm attempt to reproduce this. 441nM 330nM Peak 2.5h early at 6am Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. Modeling suggested that MR-HC15 20 mg at 2300h and 10mg at 0700 h could reproduce physiological cortisol levels (J Clin Endocrinol Metab 94: , 2009) Increase starts 2am 110nM

22 Twice daily Chronocort The circadian rhythm of cortisol Serum Cortisol nmol/l :00 19:00 23:00 03:00 07:00 11:00 15:00 19:00 23:00 03:00 07:00 Time (24 hour clock) Source: Whitaker et al Clin Endo 2014; 20mg HC 10mg HC 22

23 Cortisol has diurnal rhythm (debono and Ross 2009) Peak at 8.32am 441nM 428nM 330nM Increase starts 5am 55nM 110nM 144nM

24 Chronocort is not yet available Duocort however is What is duocort? A dual release hydrocortisone In the UK: Plenadren

25 Advertisement from BMJ 2017 Dual release hydrocortisone

26 Advertisement from BMJ 2017 Dual release hydrocortisone Depends on continued absorption for several hours Potentially dangerous in GI infections such as norovirus which might block absorption some hours after oral ingestion

27 Which of the following are VERY COMMON side effects of Plenadren A. Diarrhoea B. Nausea C. Abdominal pain D. Pruritus E. Rash Advertisement from BMJ 2017 Dual release hydrocortisone Depends on continued absorption for several hours Potentially dangerous in GI infections such as norovirus which might block absorption some hours after oral ingestion

28 Which of the following are VERY COMMON side effects of Plenadren A. Diarrhoea B. Nausea C. Abdominal pain D. Pruritus E. Rash Advertisement from BMJ 2017 Dual release hydrocortisone Depends on continues absorption for several hours Potentially dangerous in GI infections such as norovirus which might block absorption some hours after oral ingestion

29 ```` Plenadren Note exposure (area under curve) of dual release was a lot less (3972) than with the tds regimen (5163 h.nmol/l), so the exposure was actually lower.

30

31 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) (BMJ advert Sept 2017) 1000 PLENADREN IRHC Prednisolone 4mg = = =

32 ```` Plenadrin Note exposure (area under curve) of dual release was a lot less than with the tds regimen, so the dose was actually lower. Cost: 2920 per year 1909 for tds HC

33 32.79 per box of 10mg. So 800 per year now

34 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) (BMJ advert Sept 2017) 1000 PLENADREN IRHC Prednisolone 4mg = = =

35 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) (NOT BMJ advert Sept 2017) 1000 PLENADREN IRHC Prednisolone 4mg = 2920 Oct 2017 Nov = = =

36

37

38

39 March 2018

40

41 Smooth curve These peaks are thought to be harmful

42 How else can we modify hydrocortisone? Various slow release preparations (chronocort, plenadrin) are new Chronocort has a delayed release so that there is NO release for some hours Plenadren has an immediate dose and a slower late release These slow release preparations have GI side effects Need longer half life, rather than slow release.

43

44 Fludrocortisone F Half life of aldosterone is too short for safe once daily administration and using the native compound is more dangerous Fluorine does not exist in natural steroids, so its presence slows metabolism substantially Binds to both MR and GR

45 1,2 dehydrohydrocortisone MW 362 MW 360 1,2 dehydrohydrocortisone has a longer half life and is more potent than cortisol 2.3x binding affinity than cortisol Minor molecule modification improves profile

46 1,2 dehydrohydrocortisone has long half life 4mg Rapidly absorbed with half life suitable for once daily administration

47 1,2 dehydrohydrocortisone advantages 4mg Rapid absorption means that continued reliance on absorption not needed Thus infectious diarrhoea will not affect absorption during the day, unlike Plenadren Rapidly absorbed with half life suitable for once daily administration

48 1,2 dehydrohydrocortisone Rapidly absorbed Long half life, ideal for once daily administration Profile similar to circadian levels of cortisol, so good for the immune system Now available

49 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) (NOT BMJ advert Sept 2017) 1000 PLENADREN IRHC Prednisolone 4mg = 2920 Oct 2017 Nov = = 800 How much should 1,2 dihydrocortisone cost? 0.12 =

50 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) 1000 PLENADREN IRHC Prednisolone 1,2 dehydrohydrocortisone 4mg = 2920 Oct 2017 Nov = = =

51 1,2 dehydrohydrocortisone Very cost effective Rapidly absorbed Long half life, ideal for once daily administration Profile similar to circadian levels of cortisol, so good for the immune system Freely available

52 MW 362 MW 360 Prednisolone has a longer half life and is more potent than cortisol 2.3x binding affinity than cortisol

53 Journal of Applied Laboratory Medicine September 2016 Copyright 2016 by American Association for Clinical Chemistry

54 March 2018

55

56 Wednesday 7 th December 2016

57

58 NO THEY DIDN T. N=36. LIE

59 Much too high a dose

60 Results Wrong Dose of prednisolone All these have NO difference, and if anything the BP and BMI (two things known to be affected by steroids) are lower in the prednisolone group IGNORE THE ABOVE Focus on this incomplete data

61

62

63

64 Note that 5mg once daily is excessive

65

66

67

68

69 Hydrocortisone 15 mg-25 mg or cortisone acetate 20 mg-35 mg given in two to three divided doses per day is suggested for adults, with the highest dose to be given in the morning. Once- or twice-daily prednisolone 3 mg-5 mg is suggested as an alternative. correct

70 Cost of daily (=annual) treatment with PLENADREN (1 x 20mg tablet) versus immediate-release hydrocortisone TDS (2 x 10mg tablets; dosed 10mg / 5mg / 5mg) 1000 PLENADREN IRHC Prednisolone 4mg = 2920 Oct 2017 Nov = = =

71 12 th December 2016

72

73 Evidence: Why prednisolone?

74 Congenital Adrenal Hyperplasia=CAH 3mg prednisolone=20 HC

75 Prednisolone replacement Either 4mg once daily, or 3mg once daily. This would be an equivalent dose of 15-30mg hydrocortisone daily.

76 At present, however, there is no evidence of any difference between the three replacement options, so it is logical to use the most cost effective, which is prednisolone. Plenadren is the least cost effective and hence has no current place in the treatment of adrenal insufficiency. Hydrocortisone was the most cost effective option until 2008, when its price increased 60-fold, but prednisolone should now be the first line option for glucocorticoid replacement therapy.

77 Prednisolone

78 Case report: switch from HC to prednisolone

79 We now need a randomised trial To compare prednisolone, hydrocortisone and MR hydrocortisone Shire will need to support the MR hydrocortisone arm of the study We have ethical approval to do a non-randomised study. If you want to take part, you need to enrol patients who are stable on hydrocortisone, measure several markers, switch them to prednisolone, and repeat the markers after an interval. The blinded, randomised study will start next year

80 March 2018

81

82 Current recommendations For pituitary or adrenal failure, use prednisolone 4mg ONCE daily For adrenal failure, add 100mcg fludrocortisone This is now the default treatment at Imperial for patients undergoing pituitary or adrenal surgery Next time you want to start replacement steroids, write up: IV hydrocortisone (which is very cheap at 92p per vial). Once well switch to: Prednisolone 4mg daily (on waking) Fludrocortisone 100mcg daily If you believe in day curves, you can do a single prednisolone level to decide if a lower dose is appropriate.

83 3 rd May 2018

84

85

86

87

88 Current recommendations For pituitary or adrenal failure, use prednisolone 4mg ONCE daily For adrenal failure, add 100mcg fludrocortisone This is now the default treatment at Imperial for patients undergoing adrenal hypofunction Next time you want to start replacement steroids, write up: IV hydrocortisone (which is very cheap at 92p per vial). Once well switch to: Prednisolone 4mg daily (on waking) Fludrocortisone 100mcg daily If you believe in day curves, you can do a single prednisolone level to decide if a lower dose is appropriate.

89

90 Comparison with type 1 diabetes Should we aim for a low glucose, with the risk of possible fatal hypoglycaemia Or should we run the glucose a bit higher to avoid hypoglycaemia at all costs?

91 One more thought In a patient with pituitary failure, who has a cortisol of zero, what replacement should we use? The minimum possible dose, so keep titrating down as far as possible and risk possible crisis? Keep the patient safe with a slight excess such as 5mg prednisolone daily and increase the dose if the patient feels tired.

92 Tomorrow, when you see a new patient with pituitary failure you can either After giving a dose of IV hydrocortisone (92 pence), 1) Give 4mg oral prednisolone ONCE daily OR 2) Spend more than TEN TIMES as much to give 10mg HC each morning, and advise the patient to break another tablet in half, and take half and keep half till 4pm in his pocket, bearing in mind that this late peak will eventually kill him. AND there is no evidence in favour of this.