Comparison of cortisol exposures and pharmacodynamic adrenal steroid responses to hydrocortisone suspension vs. commercial tablets (original) (raw)
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International journal of pediatric endocrinology, 2016
Little is known about the comparative effects of different glucocorticoids on the adrenal and growth hormone (GH) axes in children with congenital adrenal hyperplasia (CAH). We sought to compare the effects of hydrocortisone (HC), prednisone (PDN), and dexamethasone (DEX) in children with classic CAH and to investigate a potential role of pharmacogenetics. Subjects were randomly assigned to three sequential 6-week courses of HC, PDN, and DEX, each followed by evaluation of adrenal hormones, IGF-1, GH, and body mass index (BMI). Single nucleotide polymorphism (SNP) analysis of genes in the glucocorticoid pathway was also performed. Nine prepubertal subjects aged 8.1 ± 2.3 years completed the study. Mean ACTH, androstenedione, and 17-hydroxyprogesterone (17-OHP) values were lower following the DEX arm of the study than after subjects received HC (p ≤ 0.016) or PDN (p ≤ 0.002). 17-OHP was also lower after HC than PDN (p < 0.001). There was no difference in IGF-1, GH, or change in BM...
Endocrine Connections
Objective Treatment of classic congenital adrenal hyperplasia (CAH) is necessary to compensate for glucocorticoid/mineralocorticoid deficiencies and to suppress androgen excess. Hydrocortisone (HC) is preferred in growing children with classic CAH but recommendations regarding dosage/administration are inconsistent. The aim of this study was to evaluate HC dosing in children with CAH in relation to chronological age, sex, and phenotype based on a multicenter CAH registry. Design The CAH registry was initiated in 1997 by the AQUAPE in Germany. On December 31st 2018, data from 1571 patients were included. Methods A custom-made electronic health record software is used at the participating centers. Pseudonymized data are transferred for central analysis. Parameters were selected based on current guidelines. Descriptive analyses and linear regression models were implemented with SAS 9.4. Results We identified 1288 patients on exclusive treatment with hydrocortisone three times daily (60...
The Journal of clinical endocrinology and metabolism, 2015
Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology. The primary outcome was cortisol pharmacoki...
Randomised controlled trial of growth effect of hydrocortisone in congenital adrenal hyperplasia
Archives of Disease in Childhood, 1997
The influence of 15 or 25 mg/m 2 of daily oral hydrocortisone with fludrocortisone 0.1 mg/day on growth and laboratory findings was evaluated in a prospective randomised crossover trial over 12 months in 26 children with 21-hydroxylase deficiency. Nine non-salt losers had fludrocortisone stopped for a further six month period. Height velocity was significantly decreased during treatment with 25 mg/m 2 as compared with 15 mg/m 2 . This was the most sensitive indicator of corticosteroid treatment excess. A dose dependent eVect upon plasma concentrations of 17hydroxyprogesterone, testosterone, and androstenedione was found but increased values were still detected in more than half of the determinations made during the 25 mg/m 2 period. Height velocity and 17hydroxyprogesterone concentrations were positively correlated. Growth hormone response to clonidine stimulation and insulin-like growth factor-1 concentrations were both within reference values and there was no diVerence between treatment periods. Withdrawal of fludrocortisone did not result in any diVerence for the non-salt losers. It was concluded that 25 mg/m 2 of hydrocortisone depressed growth in children with congenital adrenal hyperplasia, and that full suppression, or even normalisation, of plasma concentrations of 17-hydroxyprogesterone and androgens should not be considered a treatment goal, but instead an indication of corticosteroid treatment excess.
Journal of Endocrinology, 2001
The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time...
Monitoring steroid replacement therapy in children with congenital adrenal hyperplasia
Journal of pediatric endocrinology & metabolism : JPEM, 2017
The objective of this study was to compare the analysis of 17-hydroxyprogesterone (17-OHP) by radio-immunoassay (RIA) in serum with analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) on dried blood spot samples (DBSS) for monitoring therapy in children with congenital adrenal hyperplasia (CAH), and to investigate differences in 17-OHP values during the day. Fourteen children (8 females), median age 4.2 (0.3-16.0) years, were studied. Serum samples and DBSS were drawn before hydrocortisone dosing. 17-OHP by LC-MS/MS in DBSS were highly correlated to 17-OHP by RIA in serum, r=0.956, p<0.01. A total of 26 three-time-point series were investigated. Using only the afternoon 17-OHP values to determine the hydrocortisone doses would have led to overdosing seven times and underdosing six times. Good agreement was demonstrated between 17-OHP determination by RIA in serum and LC-MS/MS on DBSS. Multiple 17-OHP measurements per day are required to ensure sufficient hydroco...
Clinical Pharmacokinetics, 2010
Background and Objective: Adrenal insufficiency is caused by primary adrenal failure or by impairment of the corticotropic axis. In both situations, cortisol secretion is deficient, and hydrocortisone is a logical replacement therapy. However, no consensus guideline for dosing has been published, and clinicians adapt the dose empirically after only a clinical evaluation. Under this regimen, some patients receiving an inappropriately high dose of cortisol feel comfortable and also have an increased risk of adverse effects. We performed a pharmacokinetic study of cortisol in patients with adrenal insufficiency to evaluate plasma concentrations when the dosing was based on clinical examination and to develop a model allowing optimization of drug dosing. Study Design: This was a prospective, open-label study in two endocrinology departments and a clinical investigation centre (Assistance Publique Hoˆpitaux de Marseille, Marseille, France). Methods: Fifty patients with primary (n = 20) or secondary (n = 30) adrenal insufficiency were recruited. All patients were given their usual hydrocortisone replacement regimen. Blood samples for cortisol measurements were drawn at 0600, and 0000 h. The observed values were compared with the known physiological range throughout the day (0800, 1600 and 0000 h). A population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling software (NONMEM Ò ). The final pharmacokinetic model was then used to simulate several hydrocortisone dosing scenarios. Results: Thirteen different treatment regimens for 50 patients were observed. The cortisol plasma concentrations were compared with the physiological range and showed that 79%, 55% and 45% of patients were over-or under-treated at 0800, 1600 and 2400 h, respectively. The cortisol concentrations showed wide variability and were best described using a one-compartment model with zero-order input and first-order elimination. The pharmacokinetic parameters (intersubject variability) were the following: duration of absorption 0.54 hour, volume of distribution 38.7 L (39.7%) and clearance 12.1 L h (23.2%). The proportional residual error was 32.3%. This final model was then used to simulate 18 different dosing regimens. The regimen with the highest proportion of simulated patients within the physiological targets was 10 + 5 + 5 mg at 0730, 1200 and 1630 h, respectively. However, even with this regimen, about 54%, 44% and 32% of patients would remain over-or under-treated at 0800, 1600 and 2400 h, respectively. Conclusions: Most patients with adrenal insufficiency are imperfectly treated with hydrocortisone relative to their plasma cortisol concentrations. Using simulation, a standard dosing regimen is suggested, which increases the proportion of patients within the physiological target concentrations. However, an individualized dose adjustment would be more accurate.
The Journal of Clinical Endocrinology & Metabolism, 2002
We have analyzed the kinetics of salivary cortisol (F) and 17-hydoxyprogesterone (17OHP) after a single oral administration of hydrocortisone (HC; 10 mg; 0700 h) in healthy male volunteers (n ؍ 10; 18-29 yr) and in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (males, n ؍ 7; females, n ؍ 3; 8.5-20.4 yr). The HC doses, related to body surface area, ranged from 6.3-9.2 mg/m 2 in controls and from 4.2-10.7 mg/m 2 in CAH patients. Saliva was collected over 5 h (at intervals of 15-30 min), and the steroids were measured with adapted RIAs. In healthy controls, maximal cortisol values (250.3 ؎ 35.9 nmol/liter) were reached after 30 min. Values showed a monophasic decrease. A t 1/2 of 94.5 min was calculated. The proportion of the HC dose in the total area under the curve was 71.2 ؎ 3.2%. For 17OHP, a monophasic decrease was found, with a minimum level of 48 ؎ 27 pmol/liter after 300 min. In CAH patients the salivary steroid profiles showed individual kinetics (maximal cortisol values ranged from 107-726 nmol/liter). Here a monophasic decrease was found with a shorter t 1/2 of 56.4 min. The HC dose proportion in the area under the curve was 88.3 ؎ 6%. 17OHP showed biphasic courses with a decrease to the minimum 17OHP level after 210 min at the latest and a subsequent gradual increase. Our findings of limited normalization of the adrenal cortex by oral HC administration underlines the necessity of optimizing therapy control and indicates the usefulness of kinetic studies for the judgement of therapy in CAH patients.
Medicina, 2002
The effect of the dose of oral hydrocortisone on stature growth rate of patients with the salt losing form of congenital adrenal hyperplasia and adequate electrolyte balance was here assessed. Thirty patients (21 girls and 9 boys) were followed longitudinally for 0.52 to 8.64 years, between chronological ages 0.35 and 8.64 years. Nine consecutive periods (Ps) of follow up were defined in order to compare two auxological parameters, height (H) at the end of a follow up P and delta H standard deviation score (SDS). According to growth rate during a particular P, two types of Ps were defined: Ps with delta H SDS > -0.5 (Group 1, satisfactory growth rate) and Ps with delta H SDS = or < -0.5 (Group 2, poor growth rate). A cut off value of 18.5 mg/m2/day of oral hydrocortisone (95% CI upper limit of group 1) was defined to separate acceptable from excessive doses. In P2, mean (+/- SD) H SDS (-1.81 +/- 1.15) was significantly lower than in any of the other Ps (p < 0.001). In P1 an...
Quality of compounded hydrocortisone capsules used in the treatment of children
European journal of endocrinology, 2017
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. 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 high-performance liquid chromatography with ultraviolet (HPLC-UV) detection method was performed based on the European Pharmacop...