Immediate-release Hydrocortisone Research Articles

Multiple dosing of immediate-release hydrocortisone is associated with a greater risk of hypothalamic-pituitary-adrenal axis suppression when compared to low-dose prednisolone when weaning in steroid-induced adrenal insufficiency

Multiple dosing of immediate-release hydrocortisone is associated with a greater risk of hypothalamic-pituitary-adrenal axis suppression when compared to low-dose prednisolone when weaning in steroid-induced adrenal insufficiency

SAT302 Circulating And Urinary Metabolites Associated With Total Exposure Of Cortisol And Cortisol Time Profile

Abstract Disclosure: J. McQueen: None. T. Garner: None. D. Chantzichristos: None. O. Ragnarsson: None. R. Bergthorsdottir: None. S. Skrtic: None. A. Stevens: None. G. Johannsson: None. The detrimental effects of excess cortisol exposure are well known, but the disruption of the circadian rhythm itself has also been associated with cardiometabolic and mental disorders. The aim of this study was to better understand these outcomes by identifying metabolites associated with total exposure of cortisol and cortisol time profile separately. This was a hypothesis-generating study using a randomized, two-armed, 12-week cross-over study comparing once-daily (OD) dual-release hydrocortisone tablet treatment with the same daily dose of thrice-daily (TID) conventional immediate-release hydrocortisone tablet treatment. Eighteen patients with primary adrenal insufficiency, who performed a full 24h in-house pharmacokinetic (PK) serum cortisol and urinary free cortisol (UFC) profiling, were included. The total exposure of cortisol was calculated by the area under the curve (AUC) of the observed cortisol concentration over 24h. To describe the variability of the cortisol time profile, the lag-1 autocorrelation (AUTO) of the cortisol concentration was calculated. Metabolites in serum and urine were analyzed using gas and liquid chromatography-mass spectrometry (GC-MS, LC-MS). Analyses were performed in negative and positive mode, and with targeted and untargeted approach. The relationship between AUC, AUTO and expression of metabolites was assessed using a Bayesian generalized linear model. The total exposure of cortisol was 20% higher during TID treatment. The AUTO was lower, reflecting a larger variability during TID compared to OD. In both serum and urine, a total of 775 metabolites were significantly associated with AUC and 479 with AUTO; 206 metabolites were overlapping and thus associated with both total exposure and the time profile. Serum GC-MS identified 55 metabolites correlated with AUC and 24 with AUTO. Among them, 12 metabolites were uniquely correlated with AUTO. Pathway analysis of these metabolites showed a high impact on the taurine and hypotaurine metabolism, and the primary bile acid biosynthesis. Pathway analysis on metabolites uniquely correlated with AUTO, identified in serum using LC-MS, also showed an impact on the primary bile acid biosynthesis, as well as the cysteine and methionine metabolism. Urinary metabolomics identified 21 metabolites correlated with AUC and 2 with AUTO. Pathway analysis of the metabolites in urine uniquely correlated with AUC, showed an impact on the ascorbate and aldarate metabolism, as well as the synthesis and degradation of ketone bodies. Our study identified circulating and urinary metabolites uniquely correlated with total exposure of cortisol and cortisol time profile, respectively. The study results therefore support that the total exposure and the time profile of cortisol may have different metabolic effects. The outcome of the study may be a step towards identifying novel biomarkers of the action of cortisol. Presentation: Saturday, June 17, 2023

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy.

Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo. Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls. Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue. Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Effects of the therapy shift from cortisone acetate to modified-release hydrocortisone in a group of patients with adrenal insufficiency.

Patients with adrenal insufficiency (AI) may be exposed to supraphysiological glucocorticoids levels during standard treatment with cortisone acetate (CA) or immediate-release hydrocortisone (IR-HC). Recent studies, predominantly including patients in IR-HC treatment, suggested that modified-release hydrocortisone (MRH) provide a more physiological cortisol rhythm, improving metabolic control and quality of life. Our primary aim was to assess clinical and biochemical modifications in patients shifted from CA to MRH. We designed a retrospective longitudinal study, enrolling 45 AI patients (22 primary and 23 secondary AI) treated exclusively with CA thrice daily, shifted to MRH once daily; 29/45 patients concluded at least 18-months follow-up (MRH-group). We recruited 35 AI patients continuing CA as a control group (CA-group). Biochemical and clinical data, including metabolic parameters, bone quality, and symptoms of under- or overtreatment were collected. In 24 patients, a daily salivary cortisol curve (SCC) performed before and one month after shifting to MRH was compared to healthy subjects (HS). No significant changes in glycometabolic and bone parameters were observed both in MRH and CA-groups during a median follow-up of 35 months. A more frequent decrease in blood pressure values (23.1% vs 2.8%, p=0.04) and improvement of under- or overtreatment symptoms were observed in MRH vs CA-group. The SCC showed a significant steroid overexposure in both CA and MRH-groups compared to HS [AUC (area under the curve) = 74.4 ± 38.1 nmol×hr/L and 94.6 ± 62.5 nmol×hr/L respectively, vs 44.1 ± 8.4 nmol×hr/L, p<0.01 for both comparisons], although SCC profile was more similar to HS in MRH-group. In our experience, patients shifted from CA to equivalent doses of MRH do not show significant glycometabolic modifications but blood pressure control and symptoms of over-or undertreatment may improve. The lack of amelioration in glucose metabolism and total cortisol daily exposure could suggest the need for a dose reduction when shifting from CA to MRH, due to their different pharmacokinetics.

PSAT087 A de Novo Model for Measuring Long-Term Health Effects of Modified-Release Hydrocortisone Capsules in Adult and Adolescent Patients With Classic Congenital Adrenal Hyperplasia

Abstract Objectives Classic congenital adrenal hyperplasia (C-CAH) is a rare condition caused by enzyme deficiency in cortisol biosynthesis. The condition is characterised by adrenal insufficiency and androgen excess and is associated with numerous disease- and treatment-related comorbidities that impact the length and quality of a patient's life. A de novo model was developed to investigate the long-term health effects of modified-release hydrocortisone capsules (Efmody® / MR-HC) compared to the standard glucocorticoid replacement therapies (including immediate-release hydrocortisone, dexamethasone, and prednisolone) currently used to treat patients with C-CAH. Methods The model is structured as a series of sub-models reflecting key comorbidities in C-CAH: adrenal crisis, cardiovascular disease, bone health, height (adolescents only), obesity, diabetes and infertility. Effects of both disease, i.e. where cortisol and/or androgen levels are too high or low, and the impact of treatment, i.e. physiological or supraphysiological steroid dosing, on each comorbidity are considered where relevant. The model captures accumulating health outcomes from each sub-model and allows quantification of overall impact on health-related quality of life (HRQoL) and mortality. The population is adolescent (&amp;gt;12 years onwards) and adult patients with C-CAH. The intervention is MR-HC, and comparator is standard glucocorticoid replacement therapies currently used in C-CAH. Model inputs, which were composed of MR-HC clinical trial data, published literature values, and clinical opinion, and the modelling approach were validated with seven European clinical experts. The model accumulates the health effect, which is measured as life-years (LYs) and quality-adjusted life years (QALYs), over a lifetime time horizon, from the ages of 12 to 100 years old. Results The model demonstrates that the treatment of C-CAH with standard glucocorticoid replacement therapies known to provide poor hormonal disease control and exposure to supraphysiological steroid dosing long-term have a substantial negative impact on HRQoL and life-expectancy in C-CAH, with modelled outcomes lower than those published for general population. Improved hormonal disease control and physiological steroid dosing with MR-HC compared to standard glucocorticoid replacement therapies result in improvements across the key comorbidities in patients with C-CAH. Quality-adjusted life year (QALY) gains are particularly driven by the reduction in adrenal crises, along with improved growth in the adolescent population and better weight control. Overall, the model demonstrates that long-term treatment of patients with C-CAH with MR-HC, compared to standard glucocorticoid replacement therapies, is expected to extend life by 7.58 years, and results in an additional 3.21 QALYs. Conclusion The model demonstrates that better hormonal disease control without exposing patients to supraphysiological steroid dosing with MR-HC improves key comorbidities in C-CAH resulting in improvement in both the length and the quality of life of patients with C-CAH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Development and verification of an endogenous PBPK model to inform hydrocortisone replacement dosing in children and adults with cortisol deficiency

The goal of hormone replacement is to mirror physiology. Hydrocortisone granules and modified release formulations are being developed to optimise cortisol replacement in the rare disease of adrenal insufficiency. To facilitate clinical development, we built and verified a physiologically based pharmacokinetic (PBPK) model for the endogenous hormone cortisol (hydrocortisone) in healthy adults, and children and adults with adrenal insufficiency.The model predicted immediate-release hydrocortisone pharmacokinetics in adults across the dose range 0.5 to 20 mg, with predicted/observed AUCs within 0.8 to 1.25-fold. The model also tightly predicted pharmacokinetic parameters for modified-release formulations, with AUCs within 0.8 to 1.25-fold after single and multiple dosing. Predicted modified-release formulation pharmacokinetics (PK) in 12 to 18-year olds showed PK to be similar to adults.This hydrocortisone PBPK model is a useful tool to predict adult and paediatric pharmacokinetics of both immediate- and modified-release hydrocortisone formulations, and develop clinical dosing regimens.

A Prospective Cross-Over Study of Tissue Glucocorticoid Metabolism in Patients With Adrenal Insufficiency: The Effects of Dual-Release Hydrocortisone Therapy

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that GC metabolism is altered in patients with AI due to the non-physiological pattern of current immediate-release hydrocortisone (IR-HC) replacement therapy. The use of once-daily dual-release hydrocortisone (DR-HC) preparation (Plenadren®) offers a more physiological cortisol profile and may alter GC metabolism in vivo.Study Design and Methods: Prospective cross-over study assessing impact of 12 weeks of DR-HC on tissue GC metabolism (using urinary steroid metabolomics, serum cortisol generation curves and adipose tissue biopsies) in 51 patients with AI (primary and secondary) and compared to age-and BMI-matched controls. Results: Patients with AI (n=51) receiving immediate-release HC (IR-HC) had a higher median 24-hour excretion of urinary cortisol compared to healthy controls [72.1µg/24hrs (IQR 43.6–124.2) vs 51.85 (35.5–72.3), p=0.02],with a lower global activity of 11β-HSD2 and higher activity of 5-alpha reductase. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary F and total GC metabolite excretion, which was most significant in the evening on diurnal urine sampling. There was an increase in global 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered post-DR-HC but there was a significant reduction in gene expression of 11β-HSD1 in subcutaneous adipose tissue. Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI. This is driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.

SUN-358 Dual Release Hydrocortisone as a New Treatment for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

In patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, long-acting glucocorticoids (GCs) and/or multiple daily dose short-acting GCs are historically suggested to disease management. However, these treatment strategies are generally associated with GC overexposure, which may induce metabolic syndrome (MS) and impairment of quality of life (QoL), and poor treatment compliance (TC). Dual-release hydrocortisone (DR-HC) with a generally once-daily administration has never been evaluated in cohorts of patients with CAH. The current study aimed at investigating the impact of the switch from conventional GCs to DR-HC on 12-month metabolic and androgens profile, QoL and TC in 39 CAH patients (26F, 13M, 18-50 years, 25 treated with immediate release hydrocortisone (IR-HC), 7 with prednisone, 3 with cortisone acetate, 3 with dexamethasone (DMX), one with IR-HC and DMX). The same cohort, stably treated with conventional GCs, was evaluated during the 12 months before the switch. In the switched cohort, at 12-month-follow-up total (p=0.028) and LDL-cholesterol (p=0.001) were significantly improved, and the diagnosis of MS, performed in two patients at baseline, was not confirmed in one patient. Interestingly, no significant increase in adrenal androgens and no clinical worsening of symptoms and signs related to hyperandrogenism in females were observed. QoL did not significantly changed, whereas TC significantly improved (p=0.001) during the year of DR-HC treatment. Conversely, no significant changes were observed during the control period before the treatment switch. In conclusion, in CAH patients the switch from conventional GCs to DR-HC appears able to induce a beneficial effect on lipid profile, MS and TC, surprisingly maintaining an optimal control of androgen levels.

Modified-Release Hydrocortisone: Is It Time to Change Clinical Practice?

The appreciation of the unacceptable outcomes of patients with adrenal insufficiency has brought new developments in glucocorticoid replacement therapy. Efforts have moved beyond simple dose adjustments of the traditional immediate-release hydrocortisone to new formulations of hydrocortisone aimed at mimicking the circadian pattern of physiological glucocorticoid release. The present report has briefly summarized the evidence base behind recent studies that have reported benefits using modified-release preparations and set this in context for today’s clinical practice.

Glucocorticoid management of adrenal insufficiency in the United Kingdom: assessment using real-world data.

Background and objectivesGlucocorticoids are used to manage adrenal insufficiency (AI). We describe treatments used in the United Kingdom and real-world clinical outcomes for each treatment.MethodsWe used 2010–2016 primary care data from The Health Improvement Network (THIN). Descriptive analyses were conducted, and differences in variables between patients prescribed immediate-release hydrocortisone (IR HC), prednisolone or modified-release hydrocortisone (MR HC) were assessed using Fisher’s exact test.ResultsOverall, 2648 patients were included: 1912 on IR HC (72%), 691 on prednisolone (26%) and 45 (2%) on MR HC. A total of 1174 (44.3%) had primary and 1150 (43.4%) had secondary AI. Patients on prednisolone were older (P < 0.001) and had a greater history of smoking (292/691, P < 0.001) and CVD (275/691, P < 0.001). Patients on MR HC had more PCOS (3/45, P = 0.001) and diabetes (27/45, P = 0.004). The number of GP visits/patient/year was 6.50 in IR HC, 9.54 in prednisolone and 9.11 in MR HC cohorts. The mean number of A&E visits and inpatient and outpatient hospital admissions ranged from 0.42 to 0.93 visits/patient/year. The mean number of adrenal crises/patient/year was between 0.02 and 0.03 for all cohorts.ConclusionIR HC is most commonly used for the management of AI in the United Kingdom, followed by prednisolone. Few patients receive MR HC. The prednisolone and MR HC cohorts displayed a greater prevalence of vascular risk factors compared with IR HC. The occurrence of AC and primary and secondary resource use were similar between treatment cohorts, and they indicate significant resource utilisation. Improved treatment and management of patients with AI is needed.

Impact of food, alcohol and pH on modified-release hydrocortisone developed to treat congenital adrenal hyperplasia.

BackgroundWe developed a modified-release hydrocortisone, Chronocort, to replace the cortisol rhythm in patients with congenital adrenal hyperplasia. Food, alcohol and pH affect drug absorption, and it is important to assess their impact when replicating a physiological rhythm.Subjects and methodsIn vitro dissolution to study impact of alcohol and pH on Chronocort. A phase 1, three-period, cross over study in 18 volunteers to assess the impact of food on Chronocort and to compare bioavailability to immediate-release hydrocortisone.ResultsIn vitro dissolution of Chronocort was not affected by gastrointestinal pH up to 6.0 nor by an alcohol content up to 20% v/v. Food delayed and reduced the rate of absorption of Chronocort as reflected by a longer Tmax (fed vs fasted: 6.75 h vs 4.5 h, P = 0005) and lower Cmax (549.49 nmol/L vs 708.46 nmol/L, ratio 77% with CI 71–85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0t for fed/fasted was 108.33% (102.30–114.72%). Cortisol exposure was higher for Chronocort compared to immediate-release hydrocortisone: Geo LSmean ratios (CI) 118.83% (111.58–126.54%); however, derived free cortisol showed cortisol exposure CIs were within 80.0–125.0%: Geo LSmean ratio (CI) for AUC0t 112.73% (105.33–120.65%).ConclusionsGastric pH ≤6.0 and alcohol do not affect hydrocortisone release from Chronocort. Food delays Chronocort absorption, but cortisol exposure is similar in the fasted and fed state and exposure as assessed by free cortisol is similar between Chronocort and immediate-release hydrocortisone.

What is the best approach to tailoring hydrocortisone dose to meet patient needs in 2012?

Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adrenal insufficiency. Cortisol has a diurnal rhythm regulated by the central body clock and this rhythm is a metabolic signal for peripheral tissue clocks. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance. A general principle in endocrinology is to replace hormones to replicate physiological concentrations; however, the pharmacokinetics of oral immediate-release hydrocortisone make it impossible to fully mimic the cortisol rhythm and patients still have an increased morbidity and mortality despite replacement. Traditionally, physicians have replaced hydrocortisone with a total daily dose based on the diurnal 24-h cortisol production rate with hydrocortisone given twice or thrice daily, with the highest dose first thing in the morning. Monitoring treatment and dose titration has been much debated with some clinicians using cortisol day curves and others relying on clinical symptoms. The main challenge is that there is no established biomarker of cortisol activity. In addressing the clinical question, we have taken the view that an understanding of the cortisol circadian rhythm and hydrocortisone pharmacokinetics is essential when tailoring hydrocortisone dose. Using this approach, we have developed a thrice daily, weight-related, dosing regimen and a pharmacokinetic and clinical method to monitor treatment. Our argument for replicating the cortisol circadian rhythm is based on the observation that disruption of the rhythm is associated with ill health, and the few studies that have compared different treatment regimens. Further studies are required to definitively test the benefits of replacing the cortisol circadian rhythm in patients with adrenal insufficiency.

Dual-release Hydrocortisone in Addison’s Disease—A Review of the Literature

In patients with adrenal insufficiency, glucocorticoids (GCs) are insufficiently secreted and GC replacement is essential for health and, indeed, life. Despite GC-replacement therapy, patients with adrenal insufficiency have a greater cardiovascular risk than the general population, and suffer from impaired health-related quality of life. Although the aim of the replacement GC therapy is to reproduce as much as possible the physiologic pattern of cortisol secretion by the normal adrenal gland, the pharmacokinetics of available oral immediate-release hydrocortisone or cortisone make it impossible to fully mimic the cortisol rhythm. Therefore, there is an unmet clinical need for the development of novel pharmaceutical preparations of hydrocortisone, in order to guarantee a more physiologic serum cortisol concentration time-profile, and to improve the long-term outcome in patients under GC substitution therapy.

Review: Replication of cortisol circadian rhythm: new advances in hydrocortisone replacement therapy

Cortisol has one of the most distinct and fascinating circadian rhythms in human physiology. This is regulated by the central clock located in the suprachiasmatic nucleus of the hypothalamus. It has been suggested that cortisol acts as a secondary messenger between central and peripheral clocks, hence its importance in the synchronization of body circadian rhythms. Conventional immediate-release hydrocortisone, either at twice- or thrice-daily doses, is not capable of replicating physiological cortisol circadian rhythm and patients with adrenal insufficiency or congenital adrenal hyperplasia still suffer from a poor quality of life and increased mortality. Novel treatments for replacement therapy are therefore essential. Proof-of-concept studies using hydrocortisone infusions suggest that the circadian delivery of hydrocortisone may improve biochemical control and life quality in patients lacking cortisol with an impaired cortisol rhythm. Recently oral formulations of modified-release hydrocortisone are being developed and it has been shown that it is possible to replicate cortisol circadian rhythm and also achieve better control of morning androgen levels. These new drug therapies are promising and potentially offer a more effective treatment with less adverse effects. Definite improvements clearly need to be established in future clinical trials.

Dual-release Hydrocortisone in Addison's Disease - A Review of the Literature.

In patients with adrenal insufficiency, glucocorticoids (GCs) are insufficiently secreted and GC replacement is essential for health and, indeed, life. Despite GC-replacement therapy, patients with adrenal insufficiency have a greater cardiovascular risk than the general population, and suffer from impaired health-related quality of life. Although the aim of the replacement GC therapy is to reproduce as much as possible the physiological pattern of cortisol secretion by the normal adrenal gland, the pharmacokinetics of available oral immediate-release hydrocortisone or cortisone make it impossible to fully mimic the cortisol rhythm. Therefore, there is an unmet clinical need for the development of novel pharmaceutical preparations of hydrocortisone, in order to guarantee a more physiological serum cortisol concentration time-profile, and to improve the long-term outcome in patients under GC substitution therapy.

Novel strategies for hydrocortisone replacement

Current therapy with immediate-release hydrocortisone is the most commonly used regimen for replacement in patients with primary and secondary adrenal insufficiency. However, conventional hydrocortisone cannot provide the physiological rhythm of cortisol release. Physicians have used fixed twice- or thrice-daily doses, but these regimens inevitably result in temporary over- or under-replacement. Patients with adrenal insufficiency, although on treatment, have a poor quality of life and an increased mortality. Optimization of current treatment has been attempted with thrice-daily, weight-related dosing, but this still fails to simulate the normal diurnal rhythm of cortisol. Recent research has investigated circadian hydrocortisone therapy imitating the physiological cortisol rhythm. Proof-of-concept studies using hydrocortisone infusions predict improvements in biochemical control and quality of life. Now delayed and sustained release oral formulations of hydrocortisone are being developed, and these offer a more practical and effective solution for patients with adrenal insufficiency and congenital adrenal hyperplasia.

Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles

Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. The study was performed at a Clinical Research Facility. Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.