ECE2023 Oral Communications Oral Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)
Switching patients with Congenital Adrenal Hyperplasia to Modified release hydrocortisone capsules: relative bioavailability and disease control
Richard John M Ross 1 , Aled Rees 2 , Deborah P. Merke 3 , Wiebke Arlt 4 , Aude Brac De La Perriere 5 , Angelica Lindén Hirschberg 6 , Anders Juul 7 , John D. C. Newell-Price 1 , Colin Graham Perry 8 , Alessandro Prete 9 , Nicole Reisch 10 , Monica Stikkelbroeck 11 , Philippe A. Touraine 12 , Ashwini Mallappa 13 , Naila Aslam 14 , Helen Coope 14 & John Porter 14
1The University of Sheffield, United Kingdom; 2Cardiff University, United Kingdom; 3NIH Clinical Center, Bethesda, United States; 4MRC London Institute of Medical Sciences, United Kingdom; 5Louis Pradel Hospital, Bron, France; 6Karolinska University Hospital, Sweden; 7Rigshospitalet, København, Denmark; 8Queen Elizabeth University Hospital, United Kingdom; 9University of Birmingham, United Kingdom; 10Department of Internal Medicine II, Gießen, Germany; 11Radboud University Nijmegen, Nijmegen, Netherlands; 12University Hospitals Pitié Salpêtrière – Charles Foix, Paris, France; 13AstraZeneca, Gaithersburg, United States; 14Diurnal Ltd, a Neurocrine Biosciences Company, Cardiff, United Kingdom
Background: Modified-release hydrocortisone (MRHC) capsules (Efmody, Diurnal Ltd, Cardiff, UK), have been developed to replicate the cortisol diurnal rhythm and shown to improve CAH disease control1. We have examined relative bioavailability of MRHC and disease control of congenital adrenal hyperplasia (CAH) patients switched from standard therapy to MRHC.
Methods: An open label, randomised, 2 period, crossover study comparing the relative bioavailability of MRHC capsules with immediate-release hydrocortisone tablets (Cortef, Pfizer) in dexamethasone-suppressed healthy volunteers was performed (NCT03343327). The Primary Endpoint was area under the cortisol concentration time curve extrapolated to infinity (AUC0-inf), with bioequivalence considered met if the ratio AUC0-inf was between 80-125%. For disease control in classic CAH patients switched to MRHC, we reviewed data from the phase 3 randomised study of standard treatment versus MRHC (NCT02716818). Patients were randomised either to continue standard treatment or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose×5; dexamethasone×80)1. Patients were assessed at baseline and after 4 weeks by 24 hr 2-hourly sampling of 17-hydroxyprogesterone (17OHP) with change from baseline in the natural log 24 hr 17OHP standard deviation score (SDS) profile calculated (17OHP SDS 24-hour profile).
Results: 24 subjects completed the relative bioavailability study. 20 mg MRHC capsules showed AUC bioequivalence to 20 mg reference hydrocortisone: Mean AUC0-inf was 2650 vs 2450 h×nmol/l, ratio of 108% (90% confidence interval (CI) 103 – 113%). In the phase 3 study, 122 patients were recruited of which 105 were included in the 4-week analysis; standard treatment (n=52) MRHC at the same dose as standard treatment (n=53). The mean 9am 17OHP at baseline vs 4 weeks was: 41 vs 6 (nmol/l) for the MRHC group and 21 vs 18 (nmol/l) in the standard treatment group. At 4 weeks, a greater reduction in the 17OHP SDS 24-hour profile was observed in the MR-HC group than the standard therapy group; treatment effect (90% CI) −0.26 (-0.46 to −0.07), P=0.007. There were no adrenal crises in the MRHC group and 3 in the standard treatment group for the whole phase 3 cohort over 6 months.
Conclusions: MRHC capsules are bioequivalent to immediate release hydrocortisone for AUC, however the more physiological exposure means that switching patients from standard treatment to MRHC at the same hydrocortisone dose equivalent results in improved CAH control. The incidence of adrenal crisis on MRHC is at the lower end of that reported in cohort studies.
Reference: 1. Merke DP., JCEM 2021 106 e2063-e2077.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more