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

BACKGROUND: We 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 METHODS: In 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. RESULTS: In 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 hrs vs 4.5 hrs, p=0005) and lower Cmax (549.49 vs 708.46, nmol/L, ratio 77% with CI 71 - 85). Cortisol exposure was similar in fed and fasted state: Geo LSmean ratio (CI) AUC0 t 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 AUC0 t 112.73% (105.33 - 120.65%). CONCLUSIONS: Gastric pH ≤ 6.0 and alcohol do not effect 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

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency

Chronotherapy based on modified-release hydrocortisone to restore the physiological cortisol diurnal rhythm

In this inspirational note, we describe the development of an endocrine chronotherapy to restore the physiological rhythm of the essential adrenal stress hormone, cortisol. The challenges included demonstrating the circadian rhythm of the drug target, creating a drug formulation that replicated that rhythm and then proving benefit in clinical trials. The physiological cortisol circadian rhythm is well defined with cortisol levels high on waking and low on going to sleep. We experimented with different formulation technologies including modified-release tablets and multi-particulates to replicate the cortisol rhythm where absent through disease. We describe the development of Efmody®, a modified-release formulation of hydrocortisone, which replicates the cortisol diurnal rhythm and improves the disease control of congenital adrenal hyperplasia, the commonest hereditary form of adrenal insufficiency. This program shows it is possible, through modified-release technology, to treat chronic endocrine diseases with physiological replacement to preserve health for life

Bioavailability of oral hydrocortisone corrected for binding proteins and measured by LC-MS/MS using serum cortisol and salivary cortisone

Context: The assessment absolute bioavailability of oral hydrocortisone is complicated by its saturable binding to cortisol binding globulin (CBG). Previous assessment of bioavailability used a cortisol radioimmunoassay which has cross reactivity with other steroids. Salivary cortisone is a measure of free cortisol and LC-MS/MS is the gold standard method for measuring steroids. We here report the absolute bioavailability of hydrocortisone calculated using serum cortisol and salivary cortisone measured by LC-MS/MS. Methods: 14 healthy male dexamethasone suppressed volunteers were administered 20 mg hydrocortisone either intravenously or orally by tablet. Samples of serum and saliva were taken and measured for cortisol and cortisone by LC-MS/MS. Serum cortisol was corrected for saturable binding using published data and pharmacokinetic parameters derived using the program WinNonlin. Results: The mean (95% CI) bioavailability of oral hydrocortisone calculated from serum cortisol, unbound serum cortisol and salivary cortisone was 1.00 (0.89-1.14); 0.88 (0.75-1.05); and 0.93 (0.83-1.05), respectively. Conclusion: The data confirm that, after oral administration, hydrocortisone is completely absorbed. The data derived from serum cortisol corrected for protein binding, and that from salivary cortisone, are similar supporting the concept that salivary cortisone reflects serum free cortisol levels and that salivary cortisone can be used as a non-invasive method for measuring the pharmacokinetics of hydrocortisone

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

Salivary cortisone to estimate cortisol exposure and sampling frequency required based on serum cortisol measurements

Context: Population studies frequently measure cortisol as a marker of stress and excess cortisol is associated with increased mortality. Cortisol has a circadian rhythm and frequent blood sampling is impractical to assess exposure. We investigated measuring salivary cortisone and examined sampling frequency required to determine cortisol exposure. Methods: Serum and saliva with cortisol and cortisone measured by LC-MS/MS in independent cohorts. The relationship between serum cortisol and salivary cortisone was analysed in cohort 1 using a linear mixed effects model and resulting fixed effects component was applied to cohort 2. Saliva cannot easily be collected when sleeping so we determined minimum sampling required to estimate cortisol exposure (eAUC) using 24-hour cortisol profiles (AUC24) and calculated the relative error (RE - a measure similar to the coefficient of variation) for the eAUC. Results: >90% of variability in salivary cortisone could be accounted for by change in serum cortisol. A single serum cortisol measurement was a poor estimate of AUC24 especially in the morning or last thing at night (RE > 68%), however 3 equally spaced samples gave a median RE of 0% (Interquartile range (IQR) between -15.6% and 15.1%). In patients with adrenal incidentalomas the eAUC based on 3 serum cortisol samples showed a difference between those with autonomous cortisol secretion and those without (p=0.03). Interpretation: Accepting that most people sleep 7-8 hours, using approximately 8-hourly salivary cortisone measurements provides a non-invasive method of estimating 24-hour cortisol exposure for population studies

Quality of compounded hydrocortisone capsules used in the treatment of children.

Objectives: Due to the lack of paediatric licensed formulations, children are often treated with individualized pharmacy-compounded adult medication. An international web-based survey about the types of medication in children with adrenal insufficiency (AI) revealed that the majority of paediatric physicians are using pharmacy-compounded medication to treat children with AI. Observations of loss of therapy control in children with congenital adrenal hyperplasia with compounded hydrocortisone capsules and regained control after prescribing a new hydrocortisone batch led to this "real world" evaluation of pharmacy-compounded paediatric hydrocortisone capsules. Methods: Capsule samples were collected randomly from volunteering parents of treated children suffering from congenital adrenal hyperplasia from all over Germany. Analysis of net mass and hydrocortisone content by HPLC-UV (high performance liquid chromatography) method were performed based on the European Pharmacopeia. Results: In total 61 batches were sent in. 5 batches could not be analyzed because of missing dose information, insufficient number of capsules or were not possible to be evaluated. 56 batches containing 1125 capsules were evaluated. 21.4% of the batches revealed insufficiency in uniformity of net mass or drug content and additional 3.6% failed because they did not contain the labelled drug. Conclusions: Compounded medication is a possible cause of variation of steroid doses in children with adrenal insufficiency or congenital adrenal hyperplasia, putting these vulnerable patients at risk of poor disease control and adrenal crisis. These data may apply to other individualized compounded oral medication as well, emphasizing the need for development of licensed paediatric formulations approved by regulatory authorities

Poor compliance and increased mortality, depression and healthcare costs in patients with congenital adrenal hyperplasia

Objectives To evaluate risks of depression and all-cause mortality, healthcare utilisation costs, and treatment adherence in congenital adrenal hyperplasia (CAH) in the UK. Design and Methods A retrospective, matched-cohort study using UK primary-care data from the Clinical Practice Research Datalink linked to hospital and death-certification data. Patients diagnosed with CAH and having ≥1 corticosteroid prescription were matched 1:10 to reference subjects. Risk of death and lifetime prevalence of depression were compared using Cox regression models. Direct financial costs were estimated for healthcare contacts. Treatment adherence was measured by medical possession ratio (MPR). Results 605 patients with CAH were identified; 562 were matched. 270 CAH patients (2,700 controls) were linkable to death-certificate data, with adjusted hazard ratio for all-cause mortality 5.17 (95%CI 2.81 to 9.50). Mean (SD) age at death in CAH patients was 54.8 (23.9) versus 72.8 (18.0) years in control patients. The prevalence ratio of depression in CAH versus control patients was 1.28 (95%CI 1.13 to 1.45). Mean (SD) annual healthcare costs were higher in CAH than controls: at age 0-6 years, £7,038 (£14,846) versus £2,879 (£13,972, p<0.001); 7-17 years, £3,766 (£7,494) versus £1,232 (£2,451, p<0.001); 18-40 years, £1,539 (£872) versus £1,344 (£1,620, p=0.007); and ≥41 years, £4,204 (£4,863) versus £1,651 (£2,303, p<0.001). Treatment adherence was lowest in adults, with 141 (36%) of 396 eligible patients having an MPR <80%. Conclusions This first analysis of CAH in routine UK healthcare suggests that patients with CAH have increased mortality, depression, and healthcare utilisation, and low treatment adherence

An oral lipidic native testosterone formulation that is absorbed independent of food

Context There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. Objective To develop an oral NT formulation. Design and methods A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. Results In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC0–10 h 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC0–10 h to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC0–10 h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. Conclusion This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels. Significance statement There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated an oral native testosterone that can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who do not tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men

Noncommutative quantum mechanics and Bohm's ontological interpretation

We carry out an investigation into the possibility of developing a Bohmian interpretation based on the continuous motion of point particles for noncommutative quantum mechanics. The conditions for such an interpretation to be consistent are determined, and the implications of its adoption for noncommutativity are discussed. A Bohmian analysis of the noncommutative harmonic oscillator is carried out in detail. By studying the particle motion in the oscillator orbits, we show that small-scale physics can have influence at large scales, something similar to the IR-UV mixing