Development and Testing in Healthy Adults of Oral Hydrocortisone Granules With Taste Masking for the Treatment of Neonates and Infants With Adrenal Insufficiency

Whitaker, Martin J.; Spielmann, S; Digweed, Dena; Huatan, Hiep; Eckland, D.J.A.; Johnson, Trevor N.; Tucker, Geoffrey T.; Krude, Heiko; Blankenstein, Oliver; Ross, R. J. M.

doi:10.1210/jc.2014-4060

Cited by 37 publications

(63 citation statements)

References 12 publications

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“…Due to the lack of low dose hydrocortisone preparations a variety of unlicensed hydrocortisone preparations at doses of between 0.5 and 5 mg are currently used in paediatric practice [45]. Such preparations bear the risk of significant dose variations [99].…”

Section: Novel Approaches To Glucocorticoid Replacementmentioning

confidence: 99%

“…A recent innovation of multilayered multiparticulate hydrocortisone granules (Infacort ® ), might overcome these problems in the foreseeable future. A dose of 10 mg Infacort ® has been shown to be bioequivalent to 10 mg hydrocortisone and unit doses of 0.5, 1, 2 and 5 mg have been tested in a recent phase 1 study [45]. The efficiency of this formulation needs to be tested in infants and children and will have the potential to optimise glucocorticoid replacement in this age group.…”

Section: Novel Approaches To Glucocorticoid Replacementmentioning

confidence: 99%

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Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

Webb

Krone

2015

Best Practice & Research Clinical Endocrinology & Metab

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Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive conditions leading to glucocorticoid deficiency. CAH is the most common cause of adrenal insufficiency (AI) in the paediatric population. The majority of the other forms of primary and secondary adrenal insufficiency are rare conditions. It is critical to establish the underlying aetiology of each specific condition as a wide range of additional health problems specific to the underlying disorder can be found. Following the introduction of life-saving glucocorticoid replacement sixty years ago, steroid hormone replacement regimes have been refined leading to significant reductions in glucocorticoid doses over the last two decades. These adjustments are made with the aim both of improving the current management of children and young persons and of reducing future health problems in adult life. However despite optimisation of existing glucocorticoid replacement regimens fail to mimic the physiologic circadian rhythm of glucocorticoid secretion, current efforts therefore focus on optimising replacement strategies. In addition, in recent years novel experimental therapies have been developed which target adrenal sex steroid synthesis in patients with CAH aiming to reduce co-morbidities associated with sex steroid excess. These developments will hopefully improve the health status and long-term outcomes in patients with congenital adrenal hyperplasia and adrenal insufficiency.

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Section: Novel Approaches To Glucocorticoid Replacementmentioning

confidence: 99%

Section: Novel Approaches To Glucocorticoid Replacementmentioning

confidence: 99%

Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

Webb

Krone

2015

Best Practice & Research Clinical Endocrinology & Metab

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“…The lowest dose available for hydrocortisone in the USA is a 5.0 mg tablet and a 10.0 mg tablet in Europe. However, the average dose used in paediatrics is 2.0 mg with doses as low as 0.5 mg required for neonates and infants (1). There is therefore a necessity to compound hydrocortisone for paediatric use.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…An international web-based survey was distributed through the newsletter of the European Society of Paediatric Endocrinology (ESPE) to specify their current treatment of adrenal insufficiency (AI) in neonates and children (1). Sixty-seven participants Correspondence should be addressed to O Blankenstein Email Oliver.Blankenstein@ charite.de from 16 countries, mostly from Europe, stated the use of divided licensed adult medication (60%) as off-label and prescription of individualized capsules (55%) as unlicensed use (1). The prescribed dosage varied from 0.5 mg to 5.0 mg with the vast majority of doses being 1.0 mg and 2.0 mg. Compounding is regulated by less stringent criteria than those used for licensed drugs as compounded drugs are neither approved by the EMA (European Medicines Agency) or FDA (Food and Drug Administration) nor required to demonstrate efficacy (2).…”

Section: Introductionmentioning

confidence: 99%

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Quality of compounded hydrocortisone capsules used in the treatment of children

Neumann

Burau

Spielmann

et al. 2017

European Journal of Endocrinology

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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 pharmacycompounded 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 highperformance liquid chromatography with ultraviolet (HPLC-UV) detection method was performed based on the European Pharmacopeia. Results: In a total of 61 batches that were sent, 5 batches could not be analysed because of missing dose information, insufficient number of capsules or were not possible to be evaluated. Fifty-six 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.

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Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?

Johnson¹,

2021

The Journal of Clinical Pharma

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Developing medicines for children is now established in legislation in both the United States and Europe; new drugs require pediatric study or investigation plans as part of their development. Particularly in early age groups, many developmental processes are not reflected by simple scalars such as body weight or body surface area, and even projecting doses based on simple allometric scaling can lead to significant overdoses in certain age groups. Modeling and simulation methodology, including physiologically based modeling, has evolved as part of the drug development toolkit and is being increasingly applied to various aspects of pediatric drug development. Pediatric physiologically based pharmacokinetic (PBPK) models account for the development of organs and the ontogeny of specific enzymes and transporters that determine the age‐related pharmacokinetic profiles. However, when should this approach be used, and when will simpler methods such as allometric scaling suffice in answering specific problems? The aim of this review article is to illustrate the application of allometric scaling and PBPK in pediatric drug development and explore the optimal application of the latter approach with reference to case examples. In reality, allometric scaling included as part of population pharmacokinetic and PBPK approaches are all part of a model‐informed drug development toolkit helping with decision making during the process of drug discovery and development; to that end, they should be viewed as complementary.

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Development and Testing in Healthy Adults of Oral Hydrocortisone Granules With Taste Masking for the Treatment of Neonates and Infants With Adrenal Insufficiency

Cited by 37 publications

References 12 publications

Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency

Quality of compounded hydrocortisone capsules used in the treatment of children

Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?

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