Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency.

OBJECTIVES: There is no licensed, dose-appropriate formulation of hydrocortisone for children with adrenal insufficiency (AI) and patients rely on compounded adult medication. The aim of this study was to evaluate the absorption, palatability and safety of Infacort® , an immediate-release, granule formulation of hydrocortisone with taste masking. STUDY DESIGN: Single site with satellites attended by a "flying" doctor from investigator site. Open-label, single-dose study in three consecutive child cohorts (n = 24) with AI; Cohort 1, children aged 2 to <6 years (n = 12); Cohort 2, infants aged 28 days to <2 years (n = 6); Cohort 3, neonates aged 1 to <28 days (n = 6). METHODS: Fasted children were given a single dose of Infacort® as dry granules administered directly from a capsule or spoon followed by a drink. The primary end-point was the maximum serum cortisol concentration up to 240 minutes after Infacort® administration. Secondary end-points were palatability and adverse events (AEs). RESULTS: All children showed an increase in cortisol above baseline after Infacort® (P < .0001), with geometric mean ± SD cortisol concentration at 60 minutes of 575.8 ± 299.5 nmol L-1 . There was no failure in administration of Infacort® , and 95.5% of parents/carers preferred Infacort® to their child's current medication. In 7 children who completed the palatability questionnaire, 80% of responses were very good or neutral, and 20% were adverse. No serious or severe treatment-emergent AEs were reported. CONCLUSIONS: Infacort® is well tolerated, easy to administer to neonates, infants and children and shows good absorption, with cortisol levels at 60 minutes after administration similar to physiological cortisol levels in healthy children.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

A Prospective Study of Children Aged 0-8 Years with CAH and Adrenal Insufficiency Treated with Hydrocortisone Granules.

CONTEXT: Children with congenital adrenal hyperplasia (CAH) and adrenal insufficiency (AI) require daily hydrocortisone replacement with accurate dosing. OBJECTIVE: Prospective study of efficacy and safety of hydrocortisone granules in children with AI and CAH monitored by 17-OHP (17-hydroxyprogesterone) saliva profiles. METHODS: Seventeen children with CAH (9 male) and 1 with hypopituitarism (male), aged from birth to 6 years, had their hydrocortisone medication changed from pharmacy compounded capsules to hydrocortisone granules. Patients were followed prospectively for 2 years. In children with CAH, the therapy was adjusted by 17-OHP salivary profiles every 3 months. The following parameters were recorded: hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis. RESULTS: The study medication was given thrice daily, and the median duration of treatment (range) was 795 (1-872) days, with 150 follow-up visits. Hydrocortisone doses were changed on 40/150 visits, with 32 based on salivary measurements and 8 on serum 17-OHP levels. The median daily mg/m2 hydrocortisone dose (range) at study entry for the different age groups 2-8 years, 1 month to 2 years, <28 days was 11.9 (7.2-15.5), 9.9 (8.6-12.2), and 12.0 (11.1-29.5), respectively, and at end of the study was 10.2 (7.0-14.4), 9.8 (8.9-13.1), and 8.6 (8.2-13.7), respectively. There were no trends for accelerated or reduced growth. No adrenal crises were observed despite 193 treatment-emergent adverse events, which were mainly common childhood illnesses. INTERPRETATION: This first prospective study of glucocorticoid treatment in children with AI and CAH demonstrates that accurate dosing and monitoring from birth results in hydrocortisone doses at the lower end of the recommended dose range and normal growth, without occurrence of adrenal crises.

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.

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue.

BACKGROUND: Immediate-release hydrocortisone granules in capsules for opening in pediatric-appropriate doses have recently been licensed for children with adrenal insufficiency. This study evaluated the bioavailability of hydrocortisone granules administered as sprinkles onto soft food and yogurt compared with direct administration to the back of the tongue. METHODS: Randomized, 3-period crossover study in 18 dexamethasone-suppressed healthy men. In each period, the fasted participants received 5 mg hydrocortisone granules either directly to the back of the tongue or sprinkled onto soft food (applesauce), or yogurt, followed by 240 mL of water. Serum cortisol was measured by liquid chromatography tandem mass spectometry. RESULTS: The cortisol geometric mean maximum concentration (Cmax) and area under the curve (AUC) for direct administration, sprinkles onto yogurt, and sprinkles onto soft food were: Cmax 428, 426, 427 nmol/L and AUC0-inf 859, 886, 844 h × nmol/L, and AUC0-t 853, 882, 838 h × nmol/L respectively. The 90% CI for the ratios of Cmax, AUC0-inf and AUC0-t for administration with soft food or yogurt to direct administration were well within the bioequivalent range, 80% to 125%. Median time to Cmax (Tmax) was similar between methods of administration: 0.63 hours administered directly, 0.75 hours on soft food and 0.75 hours on yogurt. No adverse events occurred during the study. CONCLUSIONS: Hydrocortisone granules administered as sprinkles onto soft food or yogurt but not mixed with these foods are bioequivalent to those administered directly to the back of the tongue. Carers, parents, or patients may choose to administer hydrocortisone granules either directly or sprinkled onto soft food or yogurt.

Patient-reported adverse effects of high-dose intravenous methylprednisolone treatment: a prospective web-based multi-center study in multiple sclerosis patients with a relapse.

In a prospective multi-center observational study, we evaluated the frequency, severity, and impact on activities of daily living (ADL) of adverse effects (AEs) of high-dose intravenous methylprednisolone (IVMP) in relapsing remitting multiple sclerosis (MS) patients with a relapse. Online self-report questionnaires stating IVMP's most common AEs were completed at baseline, the 2nd day of treatment, and 1 day and 1 week after treatment. Eighty-five patients were included, 66 completed the baseline questionnaire, and 59 completed at least one post-baseline questionnaire. Patients reported on average 4 (median) AEs; two (3.4 %) reported no AE. Most frequent was change in taste (61 %), facial flushing (61 %), sick/stomach pain (53 %), sleep disturbance (44 %), appetite change (37 %), agitation (36 %), and behavioral changes (36 %). Of all AEs, 34.3 % were severe and 37.9 % impacted on ADL. A 3-day course resulted in 4 (median) AEs and a 5-day course in 7. All patients with high disease impact had two or more AEs, compared with 79 % of those with low impact (p < 0.01). Of patients with high disability, 45 % had severe AEs, compared with 16 % of those with low disability. Severe central nervous system (CNS)-related AEs occurred two times more frequently in patients with high disease impact, and two-and-a-half times more frequently in patients with high disability. Therefore, in virtually all patients, high-dose IVMP leads to AEs, with about one of three AEs being severe with impact on ADL. Patients with high disease impact or high disability may experience more (severe) AEs, due to a higher occurrence of severe CNS-related AEs.