Comparison of immediate- and modified-release hydrocortisone to achieve therapeutic goals in congenital adrenal hyperplasia
Davide Bindellini1,2, Robin Michelet1, Yersultan Mirasbekov1,2, Wilhelm Huisinga2,3, Uta Neumann4, Oliver Blankenstein4,5, Martin Whitaker6, Richard Ross6, Charlotte Kloft1,2
1Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 2Graduate Research Training program PharMetrX, 3Institute of Mathematics, University of Potsdam, 4Charité-Universitätsmedizin Berlin, 5Labor Berlin, Charité Vivantes GmbH, 6University of Sheffield
Introduction and objectives: Congenital adrenal hyperplasia (CAH) is a rare genetic disease characterised by reduced cortisol production. Cortisol production is stimulated by adrenocorticotropic hormone (ACTH) following a circadian rhythm, while cortisol suppresses ACTH secretion via feedback inhibition to maintain homeostasis. Hence, due to reduced cortisol, CAH patients exhibit elevated ACTH concentrations, leading to increased androgens and resulting in virilisation for women and infertility for women and men [1,2]. Severe CAH can result in fatal adrenal crisis, if untreated. CAH patients often require lifelong cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) being the recommended drug [3]. The goals of HC therapy are to mimic physiological cortisol circadian rhythm and thereby to avoid ACTH excess. Immediate- and modified-release (IR and MR) HC formulations are available [4,5], yet a quantitative understanding of their effect on the ACTH-cortisol system dynamics is lacking. We compared the ability of both formulations to achieve therapeutic goals under various dosing regimens, by leveraging a previously developed healthy adult model integrating ACTH-cortisol dynamics, IR PK, and an optimised MR HC PK model [6,7]. Methods: Clinical trial data from fasted, healthy adults were leveraged (dexamethasone was administered to suppress endogenous ACTH and cortisol): Cortisol concentrations were measured following single-dose 5-30 mg of MR HC given at 23:00, or 20 mg given at 08:00 or multiple-doses of 20 mg at 23:00 and 10 mg at 07:00. This data was used to optimise the MR HC absorption model: The implementation of a gastric emptying onset function [8] followed by a fixed number of transit compartments, from 1 to 7, was evaluated . Simulations were performed for 70 kg patients and in absence of endogenous cortisol production to ensure unbiased formulation effect comparison. Dosing regimens included in the analysis were generated based on therapy settings combinations: for IR, daily doses of 15, 20 or 25 mg/day (2:1:1 ratio) with first dose administered at 05:00, 06:00 or 07:00 and dosing intervals of 4, 5 or 6 hours, while for MR, evening doses of 15, 20 or 25 mg at 22:00, 23:00 or 24:00 and morning doses of 5, 10 or 15 mg at 06:00, 07:00 or 08:00. In total, 27 IR and 48 MR dosing regimens were compared using deterministic simulations. To evaluate therapeutic goals achievement, the metrics used were ACTH AUC reduction compared to simulated untreated patient, and root mean squared error (RMSE) compared to simulated healthy cortisol profiles. To evaluate the impact of variability, the best and worst dosing regimens in terms of RMSE from each formulation were further evaluated using stochastic simulations (n=1000). Results: The use of a gastric emptying onset function followed by 4 transit compartments was best at describing MR HC absorption kinetics: Maximal gastric emptying rate constant and transit rate constant (Ktr) were assumed to be identical. Importantly, differences in absorption kinetics between evening and morning doses were identified for Ktr (1.58 h-1 and 2.56 h-1), time to reach 50% of Ktr (T50, 3.55 h and 2.56 h), and F (28.6% and 42.5%, respectively). Evaluating dosing regimens revealed the superiority of MR in reducing ACTH AUC compared to IR: The lowest ACTH AUC reduction achieved by MR dosing regimens of 85.2%, was higher than the highest reduction achieved by IR dosing regimens of 78.0%. Only for IR, the reduction of ACTH AUC was highly dependent on time of first dose, 05:00, 06:00 and 07:00, with median reduction of 71.9%, 44.0% and 20.6%, respectively. MR was superior also at mimicking healthy cortisol profiles: MR RMSE ranged from 428 to 890, compared to IR ranging from 681 to 966. Overall, MR dosing regimens yielded sufficiently high cortisol concentrations allowing for efficacious ACTH suppression even when not accurately mimicking healthy cortisol profiles. Larger variability was associated to ACTH and cortisol profiles following MR dosing regimens, yet scenarios resulting in lowest ACTH reduction were comparable with IR therapy. Conclusion: The superiority of MR HC at reducing ACTH excess typical of CAH patients and mimicking healthy cortisol profiles was shown, despite the larger variability associated with its absorption kinetics. Absorption kinetics differences for evening and morning MR HC doses were shown and were likely attributable to reduced gastrointestinal activity at night and a potential impact of posture during sleep.
[1] D.P. Merke, R.J. Auchus. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. N Engl J Med 383: 13–16 (2020). [2] H.L.C. van der Grinten, P.W. Speiser, S. Faisal Ahmed, W. Arlt, R.J. Auchus, H. Falhammar, C.E. Flück, L. Guasti, A. Huebner, B.B.M. Kortmann, N. Krone, D.P. Merke, W.L. Miller, A. Nordenström, N. Reisch, D.E. Sandberg, N.M.M.L. Stikkelbroeck, P. Touraine, A. Utari, S.A. Wudy, P.C. White. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev 43: 91–159 (2022). [3] P.W. Speiser, W. Arlt, R.J. Auchus, L.S. Baskin, G.S. Conway, D.P. Merke, H.F.L. Meyer-Bahlburg, W.L. Miller, M. Hassan Murad, S.E. Oberfield, P.C. White. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 103: 4043–4088 (2018). [4] M.J. Whitaker, S. Spielmann, D. Digweed, H. Huatan, D. Eckland, T.N. Johnson, G. Tucker, H. Krude, O. Blankenstein, R.J. Ross. Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency. J Clin Endocrinol Metab 100: 1681–1688 (2015). [5] M.J. Whitaker, M. Debono, H. Huatan, D.P. Merke, W. Arlt, R.J. Ross. An oral multi-particulate, modified release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin Endocrinol (Oxf) 80: 554 (2014). [6] D. Bindellini, R. Michelet, L.B.S. Aulin, J. Melin, U. Neumann, O. Blankenstein, W. Huisinga, M.J. Whitaker, R. Ross, C. Kloft. A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy. J Pharmacokinet Pharmacodyn 51: (2024). [7] PAGE 32 (2024) Abstr 11023 [www.page-meeting.org/?abstract=11023]. [8] B. Guiastrennec, D.P. Sonne, M. Hansen, J.I. Bagger, A. Lund, J.F. Rehfeld, O. Alskär, M.O. Karlsson, T. Vilsbøll, F.K. Knop, M. Bergstrand. Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake. CPT Pharmacometrics Syst Pharmacol 5: 692–700 (2016).