Development and Testing in Healthy Adults of Oral Hydrocortisone Granules With Taste Masking for the Treatment of Neonates and Infants With Adrenal Insufficiency
Abstract
BACKGROUND: Treatment of neonates and infants with adrenal insufficiency is unsatisfactory because unlicensed hydrocortisone formulations are used. OBJECTIVES: The objectives were to survey current hydrocortisone prescribing practice and develop a novel hydrocortisone formulation, Infacort. METHODS: The use of hydrocortisone by European pediatric endocrinologists was surveyed. Based on this, an oral hydrocortisone granule formulation, Infacort, with taste masking was developed and evaluated in vitro and then in vivo in a phase I pharmacokinetic study. RESULTS: The survey showed that pediatricians use a variety of unlicensed compounded adult medications at doses of between 0.5 and 5 mg. Infacort was formulated with a taste-masking layer stable for at least 5 minutes in aqueous media and was produced in unit doses of 0.5, 1, 2, and 5 mg. Infacort 10 mg is the bioequivalent of a 10-mg hydrocortisone tablet (mean area under the curve from zero to infinity [AUC(0-inf)] ratio, 101%; 90% confidence interval, 96-107%). Mean cortisol maximum concentration (C(max)) and AUC(0-inf) values after administration of Infacort were linear with dose and dose proportional when adjusted for saturable plasma protein binding. Subjects rated Infacort as "not good or bad" for smell (86%), feel in the mouth (71%), and taste (79%). No serious adverse events were reported. CONCLUSIONS: This phase 1 study demonstrates that Infacort is safe, well tolerated, of neutral taste, bioequivalent to hydrocortisone licensed for adults, and shows dose proportionality with respect to cortisol exposure. Infacort is expected to facilitate optimization of hydrocortisone dosing in neonates and children with adrenal insufficiency; however, clinical studies will be required to demonstrate efficacy in this patient age group.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hydrocortisone is only licensed in 10 mg and 20 mg tablet doses in the European Union.
“hydrocortisone is only licensed in 10 and 20mg tablet doses in the European Union”
From Immediate-release granule formulation of hydrocortisone, Alkindi®, for treatment of paediatric adrenal insufficiency (Infacort development programme) (2018) · cites this paper as [5]
Children are unable to swallow tablets designed for adults.
“and are unable to swallow tablets designed for adults (5).”
From Immediate-release granule formulation of hydrocortisone, Alkindi®, for treatment of paediatric adrenal insufficiency (Infacort development programme) (2018) · cites this paper as [5]
Children require hydrocortisone doses much smaller than available tablets, of the order of 1-2 mg three times daily in infants.
“children require much smaller doses (of the order of 1-2mg three times daily in infants)”
From Immediate-release granule formulation of hydrocortisone, Alkindi®, for treatment of paediatric adrenal insufficiency (Infacort development programme) (2018) · cites this paper as [5]
The phase 1 study demonstrated bioequivalence of Alkindi to immediate-release hydrocortisone.
“The study demonstrated bioequivalence of Alkindi® to immediate release hydrocortisone (Figure 2)(5).”
From Immediate-release granule formulation of hydrocortisone, Alkindi®, for treatment of paediatric adrenal insufficiency (Infacort development programme) (2018) · cites this paper as [5]
Cites
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency*
White, P. C., & Speiser, P. W. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.3.0398 · Cited by 1,432 · see citing works
Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients
Arlt, W., Willis, D. S., Wild, S. H., Krone, N., Doherty, E. J., Hahner, S., Han, T. S., Carroll, P. V., Conway, G. S., Rees, D. A., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0917 · Cited by 506 · see citing works
Self-citationClinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia
Finkielstain, G. P., Kim, M. S., Sinaii, N., Nishitani, M., Van Ryzin, C., Hill, S. C., Reynolds, J. C., Hanna, R. M., & Merke, D. P. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-2102 · Cited by 313 · see citing works
Eight-six Cases of Adison's Disease
Dunlop, D. (1963) · BMJ · doi:10.1136/bmj.2.5362.887 · Cited by 216 · see citing works
Whitaker, M. J., Debono, M., Huatan, H., Merke, D. P., Arlt, W., & Ross, R. J. (2014) · Clinical Endocrinology · doi:10.1111/cen.12316 · Cited by 121 · see citing works
Self-citationMedicines for Children: A Matter of Taste
Davies, E. H., & Tuleu, C. (2008) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2008.06.030 · Cited by 119 · see citing works
Treatment and health outcomes in adults with congenital adrenal hyperplasia
Han, T. S., Walker, B. R., Arlt, W., & Ross, R. J. (2014) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.239 · Cited by 102 · see citing works
Self-citationHan, T. S., Conway, G. S., Willis, D. S., Krone, N., Rees, D. A., Stimson, R. H., Arlt, W., Walker, B. R., Ross, R. J., & (CaHASE), T. U. K. C. A. H. A. S. E. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1486 · Cited by 65 · see citing works
Self-citationConn, J. W., Louis, L. H., & Fajans, S. S. (1951) · Science · doi:10.1126/science.113.2947.713 · Cited by 59 · see citing works
Temperature-Dependent Cortisol Distribution among the Blood Compartments in Man
Lentjes, E. G. W. M., & Romijn, F. H. T. P. M. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.2.5461 · Cited by 29 · see citing works
Kauzor, D., Spielmann, S., Ross, R. J. M., Blankenstein, O., & Kloft, C. (2014) · Endocrine Abstracts · doi:10.1530/endoabs.35.p825 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
2 of the 13 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults
Betterle, C., Presotto, F., & Furmaniak, J. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01079-6 · Cited by 139 · see citing works
An Update on Addison’s Disease
Barthel, A., Benker, G., Berens, K., Diederich, S., Manfras, B. J., Grüber, M., Kanczkowski, W., Kline, G. A., Kamvissi, V., Hahner, S., et al. (2018) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/a-0804-2715 · Cited by 115 · see citing works
Neumann, U., Whitaker, M. J., Wiegand, S., Krude, H., Porter, J., Davies, M., Digweed, D., Voet, B., Ross, R. J., & Blankenstein, O. (2018) · Clinical Endocrinology · doi:10.1111/cen.13447 · Cited by 64 · see citing works
Self-citationMadathilethu, J., Roberts, M., Peak, M., Blair, J., Prescott, R., & Ford, J. L. (2018) · BMJ Paediatrics Open · doi:10.1136/bmjpo-2017-000198 · Cited by 63 · see citing works
Webb, E. A., & Krone, N. P. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.04.002 · Cited by 59 · see citing works
Quality of compounded hydrocortisone capsules used in the treatment of children
Neumann, U., Burau, D., Spielmann, S., Whitaker, M. J., Ross, R. J., Kloft, C., & Blankenstein, O. (2017) · European Journal of Endocrinology · doi:10.1530/eje-17-0248 · Cited by 56 · see citing works
Self-citationNovel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency
Oprea, A., Bonnet, N., Pollé, O. G., & Lysy, P. A. (2019) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018818821294 · Cited by 54 · see citing works
Is physiological glucocorticoid replacement important in children?
Porter, J., Blair, J., & Ross, R. J. (2017) · Archives of Disease in Childhood · doi:10.1136/archdischild-2015-309538 · Cited by 50 · see citing works
Self-citationClinical advances in the pharmacotherapy of congenital adrenal hyperplasia
Prete, A., Auchus, R. J., & Ross, R. J. (2022) · White Rose Research Online (University of Leeds, The University of Sheffield, University of York) · Cited by 46 · see citing works
Self-citationNeumann, U., Braune, K., Whitaker, M. J., Wiegand, S., Krude, H., Porter, J., Digweed, D., Voet, B., Ross, R. J. M., & Blankenstein, O. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa626 · Cited by 38 · see citing works
Self-citationWatson, C., Webb, E. A., Kerr, S., Davies, J. H., Stirling, H., & Batchelor, H. K. (2018) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2018.04.054 · Cited by 36 · see citing works
Barillas, J. E., Eichner, D., Van Wagoner, R., & Speiser, P. W. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2017-01595 · Cited by 35 · see citing works
Melin, J., Parra-Guillen, Z. P., Michelet, R., Truong, T., Huisinga, W., Hartung, N., Hindmarsh, P., & Kloft, C. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa071 · Cited by 34 · see citing works
3D printed personalized therapies for pediatric patients affected by adrenal insufficiency
Rodríguez‐Pombo, L., Gallego-Fernández, C., Jørgensen, A. K., Parramon‐Teixidó, C. J., Cañete-Ramírez, C., Poy, M. J. C., Basit, A. W., Alvarez‐Lorenzo, C., & Goyanes, Á. (2024) · Expert Opinion on Drug Delivery · doi:10.1080/17425247.2024.2399706 · Cited by 31 · see citing works
Novel treatments for congenital adrenal hyperplasia
Schröder, M. A. M., & der Grinten, H. L. C. (2022) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-022-09717-w · Cited by 29 · see citing works
Porter, J., Withe, M., & Ross, R. J. (2018) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2018.1455496 · Cited by 26 · see citing works
Self-citationA review on taste masked multiparticulate dosage forms for paediatric
AL-Japairai, K. A. S., Almurisi, S. H., Doolaanea, A. A., Mahmood, S., Alheibshy, F., Alobaida, A., Abdul-Halim, N., & Chatterjee, B. (2022) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2022.122571 · Cited by 26 · see citing works
Johnson, T. N., & Ke, A. B. (2021) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.1834 · Cited by 25 · see citing works
Self-citationBonner, J. J., Burt, H. J., Johnson, T. N., Whitaker, M. J., Porter, J. B., & Ross, R. J. M. (2021) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2021.105913 · Cited by 21 · see citing works
Self-citationRodríguez‐Pombo, L., Carou‐Senra, P., Rodríguez-Martínez, E., Januskaite, P., Rial, C., Felix, P. C. A., Alvarez‐Lorenzo, C., Basit, A. W., & Goyanes, Á. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124005 · Cited by 18 · see citing works
Hoyer‐Kuhn, H., Huebner, A., Richter-Unruh, A., Bettendorf, M., Rohrer, T. R., Kapelari, K., Riedl, S., Mohnike, K. L., Dörr, H., Roehl, F.-W., et al. (2021) · Endocrine Connections · doi:10.1530/ec-21-0023 · Cited by 18 · see citing works
Melin, J., Parra-Guillen, Z. P., Hartung, N., Huisinga, W., Ross, R. J., Whitaker, M. J., & Kloft, C. (2018) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0575-8 · Cited by 17 · see citing works
Self-citationAl-Rayess, H., Fleissner, K., Jaber, M. M., Brundage, R. C., & Sarafoglou, K. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa091 · Cited by 17 · see citing works
Sarafoglou, K., & Auchus, R. J. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae759 · Cited by 16 · see citing works
Current and future treatment options for adrenal insufficiency
Arshad, M. F., & Debono, M. (2021) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000637 · Cited by 13 · see citing works
Nokoff, N., Buchanan, C., & Barker, J. M. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae563 · Cited by 15 · see citing works
Accuracy of hydrocortisone dose administration via nasogastric tube
Daniel, E., Whitaker, M. J., Keevil, B. G., Wales, J. K., & Ross, R. J. M. (2018) · Clinical Endocrinology · doi:10.1111/cen.13876 · Cited by 14 · see citing works
Self-citationDung, P.-T.-P., Trinh, T.-D., Nguyen, Q.-H., Nguyen, H.-M., Nguyen, N.-C., Tran, N. B., Tran, C.-S., Nguyen, T.-H.-N., & Tung, N.-T. (2023) · Journal of Microencapsulation · doi:10.1080/02652048.2023.2209639 · Cited by 12 · see citing works
Hofmanová, J., Bennett, J., Coupe, A. J., Bartlett, J. A., Monahan, A. P., & Batchelor, H. K. (2020) · Pharmaceutics · doi:10.3390/pharmaceutics12090806 · Cited by 12 · see citing works
Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue
Daniel, E., Digweed, D., Quirke, J., Voet, B., Ross, R. J. M., & Davies, M. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2018-00380 · Cited by 11 · see citing works
Self-citationCoope, H., Parviainen, L., Withe, M., Porter, J. B., & Ross, R. J. M. (2021) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2021.1903871 · Cited by 8 · see citing works
Self-citationStachanow, V., Neumann, U., Blankenstein, O., Bindellini, D., Melin, J., Ross, R. J. M., Whitaker, M. J., Huisinga, W., Michelet, R., & Kloft, C. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.819590 · Cited by 6 · see citing works
Self-citationAutoimmune Primary Adrenal Insufficiency: Understanding the Past, Present, and Future
Surani, A., & Carroll, T. B. (2025) · Endocrine Practice · doi:10.1016/j.eprac.2025.04.008 · Cited by 4 · see citing works
Reznik, Y. (2016) · La Presse Médicale · doi:10.1016/j.lpm.2016.05.007 · Cited by 4 · see citing works
Diagnosis and Management of Adrenal Insufficiency in Children and Adults
Llahana, S., Mitchelhill, I., Yeoh, P., & Quinkler, M. O. (2019) · Springer eBooks · doi:10.1007/978-3-319-99817-6_37 · Cited by 5 · see citing works
The Current Treatment Landscape for Congenital Adrenal Hyperplasia
Tonge, J. J., Bacila, I. A., & Krone, N. P. (2025) · Drugs · doi:10.1007/s40265-025-02216-7 · Cited by 3 · see citing works
The Potential of Micropellets and Mini-Tablets in Oral Pediatric Formulations with Challenging APIs
Pöllinger, N. (2025) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2025.2580359 · Cited by 3 · see citing works
Burger‐Stritt, S., & Hahner, S. (2016) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/s-0042-118276 · Cited by 3 · see citing works
Approach to the Child and Adolescent With Adrenal Insufficiency
Patti, G., Zucconi, A., Matarese, S., Tedesco, C., Panciroli, M., Napoli, F., Iorgi, N. D., & Maghnie, M. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae564 · Cited by 3 · see citing works
Bethin, K. E., Majumdar, I., & Muglia, L. J. (2024) · Springer eBooks · doi:10.1007/978-3-031-66296-6_10 · Cited by 2 · see citing works
Bethin, K. E., Majumdar, I., & Muglia, L. J. (2018) · Springer eBooks · doi:10.1007/978-3-319-73782-9_13 · Cited by 1 · see citing works
Neumann, U., Whitaker, M. J., Wiegand, S., Krude, H., Porter, J. B., Davies, M., Digweed, D., Voet, B., Ross, R. J. M., & Blankenstein, O. (2019) · Endocrine Abstracts · doi:10.1530/endoabs.65.ja5 · Cited by 1 · see citing works
Self-citationVantaggi delle nuove formulazioni di glucocorticoidi nel trattamento della sindrome adreno-genitale
Lapolla, R., & Delvecchio, M. (2021) · L Endocrinologo · doi:10.1007/s40619-021-00921-5
Betterle, C., Presotto, F., & Zanchetta, R. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00042-7
Kaye, A. D., Khaled, M. E., Bembenick, K. N., Lacey, J., Tandon, A., Kelkar, R. A., Derouen, A. G., Ballaera, C., Chandler, D., Ahmadzadeh, S., et al. (2024) · Cureus · doi:10.7759/cureus.56031
Betterle, C., Sabbadin, C., & Presotto, F. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23947-2.00056-4
Pharmacotherapeutic strategies for the management of congenital adrenal hyperplasia
Goai, W. H., & Torpy, D. J. (2026) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2026.2695099
The evolution of new approaches to the treatment of congenital adrenal hyperplasia
Merke, D. P., & Auchus, R. J. (2026) · Endocrine Reviews · doi:10.1210/endrev/bnag033
- Authors
- Whitaker, M. J., Spielmann, S., Digweed, D., Huatan, H., Eckland, D., Johnson, T. N., Tucker, G., Krude, H., Blankenstein, O., & Ross, R. J.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Diurnal (United Kingdom) (GB)
- Simcyp (United Kingdom) (GB)
- University of Sheffield (GB)
- Corresponding author
- Ross, Richard J.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-04
- Volume
- 100
- Issue
- 4
- Pages
- 1681-1688
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2078040683
- Cited by
- 48
- References
- 13
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 1 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 3 · 2015: 1
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Society of Endocrinology
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- cortisol, taste masking, oral granules, adrenal insufficiency, neonates, infants, bioequivalence, pharmacokinetics, dose proportionality, plasma protein binding, drug formulation development
- MeSH terms
- Administration, Oral, Adolescent, Adrenal Insufficiency, Adult, Dosage Forms, Humans, Hydrocortisone, Infant, Newborn, Male, Middle Aged, Palate, Taste, Therapeutic Equivalency, Cross-Over Studies, Young Adult, Healthy Volunteers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
