{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:35:13Z","timestamp":1792071313745,"version":"4.4.0"},"reference-count":28,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,5,21]],"date-time":"2021-05-21T00:00:00Z","timestamp":1621555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002752","name":"Bodossaki Foundation","doi-asserted-by":"publisher","award":["\u0391.\u03a0. 8\/366\/\u03b5\u03b4"],"award-info":[{"award-number":["\u0391.\u03a0. 8\/366\/\u03b5\u03b4"]}],"id":[{"id":"10.13039\/501100002752","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P014747\/1"],"award-info":[{"award-number":["MR\/P014747\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement of novel HC replacement therapies is the calibration of infusion pumps against cortisol levels measured in blood. However, repeated blood sampling sessions are enormously labour-intensive for both examiners and examinees. These sessions also have a cost, are time consuming and are occasionally unfeasible. To address this, we developed a pharmacokinetic model approximating the values of plasma cortisol levels at any point of the day from a limited number of plasma cortisol measurements. The model was validated using the plasma cortisol profiles of 9 subjects with disrupted endogenous GC synthetic capacity. The model accurately predicted plasma cortisol levels (mean absolute percentage error of 14%) when only four plasma cortisol measurements were provided. Although our model did not predict GC dynamics when HC was administered in a way other than subcutaneously or in individuals whose endogenous capacity to produce GCs is intact, it was found to successfully be used to support clinical trials (or practice) involving subcutaneous HC delivery in patients with reduced endogenous capacity to synthesize GCs.<\/jats:p>","DOI":"10.3390\/pharmaceutics13060769","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:01:20Z","timestamp":1621814480000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Modelling Hydrocortisone Pharmacokinetics on a Subcutaneous Pulsatile Infusion Replacement Strategy in Patients with Adrenocortical Insufficiency"],"prefix":"10.3390","volume":"13","author":[{"given":"Ioannis G.","family":"Violaris","sequence":"first","affiliation":[{"name":"Department of Electrical and Computer Engineering, University of Western Macedonia, 50131 Kozani, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kalafatakis","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK"},{"name":"Department of Informatics &amp; Telecommunications, School of Informatics &amp; Telecommunications, University of Ioannina, 47100 Arta, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5467-6036","authenticated-orcid":false,"given":"Eder","family":"Zavala","sequence":"additional","affiliation":[{"name":"Centre for Systems Modelling and Quantitative Biomedicine, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis G.","family":"Tsoulos","sequence":"additional","affiliation":[{"name":"Department of Informatics &amp; Telecommunications, School of Informatics &amp; Telecommunications, University of Ioannina, 47100 Arta, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodoros","family":"Lampros","sequence":"additional","affiliation":[{"name":"Department of Informatics &amp; Telecommunications, School of Informatics &amp; Telecommunications, University of Ioannina, 47100 Arta, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stafford L.","family":"Lightman","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6757-1698","authenticated-orcid":false,"given":"Markos G.","family":"Tsipouras","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering, University of Western Macedonia, 50131 Kozani, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0615-783X","authenticated-orcid":false,"given":"Nikolaos","family":"Giannakeas","sequence":"additional","affiliation":[{"name":"Department of Informatics &amp; Telecommunications, School of Informatics &amp; Telecommunications, University of Ioannina, 47100 Arta, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9043-1290","authenticated-orcid":false,"given":"Alexandros","family":"Tzallas","sequence":"additional","affiliation":[{"name":"Department of Informatics &amp; Telecommunications, School of Informatics &amp; Telecommunications, University of Ioannina, 47100 Arta, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1299-4116","authenticated-orcid":false,"given":"Georgina M.","family":"Russell","sequence":"additional","affiliation":[{"name":"Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.pnpbp.2017.11.020","article-title":"Glucocorticoids, genes and brain function","volume":"82","author":"Juszczak","year":"2018","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1152\/physrev.1986.66.4.1121","article-title":"Adrenal steroid receptors and actions in the nervous system","volume":"66","author":"McEwen","year":"1986","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5037","DOI":"10.1523\/JNEUROSCI.5717-09.2010","article-title":"Membrane-associated glucocorticoid activity is necessary for modulation of long-term memory via chromatin modification","volume":"30","author":"Roozendaal","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"McMaster, A., Jangani, M., Sommer, P., Han, N., Brass, A., Beesley, S., Lu, W., Berry, A., Loudon, A., and Donn, R. (2011). Ultradian cortisol pulsatility encodes a distinct; biologically important signal. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0015766"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1152\/physrev.00020.2012","article-title":"11\u03b2-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action","volume":"93","author":"Chapman","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1210\/me.2010-0073","article-title":"The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP\/p300 during ultradian ligand treatment","volume":"25","author":"George","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/nrn2914","article-title":"The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration","volume":"11","author":"Lightman","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1111\/jne.12247","article-title":"The importance of biological oscillators for hypothalamic-pituitary adrenal activity and tissue glucocorticoid response: Coordinating stress and neurobehavioural adaptation","volume":"27","author":"Russell","year":"2015","journal-title":"J. Neuroendocrinol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1677\/joe.0.1780013","article-title":"Cell- and tIssue-specific effects of corticosteroids in relation to glucocorticoid resistance: Examples from the brain","volume":"178","author":"Meijer","year":"2003","journal-title":"J. Endocrinol."},{"key":"ref_10","first-page":"1627","article-title":"Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis","volume":"277","author":"Walker","year":"2010","journal-title":"Proc. Biol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.neubiorev.2015.11.009","article-title":"Temporal control of glucocorticoid neurodynamics and its relevance for brain homeostasis; neuropathology and glucocorticoid-based therapeutics","volume":"61","author":"Kalafatakis","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/ncpendmet0051","article-title":"Management of patients with glucocorticoid deficiency","volume":"1","author":"Crown","year":"2005","journal-title":"Nat. Clin. Pract. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13063-016-1159-x","article-title":"Effects of the pattern of glucocorticoid replacement on neural processing; emotional reactivity and well-being in healthy male individuals: Study protocol for a randomised controlled trial","volume":"17","author":"Kalafatakis","year":"2016","journal-title":"Trials"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"E4091","DOI":"10.1073\/pnas.1714239115","article-title":"Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man","volume":"115","author":"Kalafatakis","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","first-page":"OC2.1","article-title":"Differential effects of subcutaneous pulsatile versus oral hydrocortisone replacement therapy on fMRI resting state and task based emotional processing in patients with primary adrenal insufficiency","volume":"65","author":"Russell","year":"2019","journal-title":"Endocrine Abstracts"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/cen.12470","article-title":"Subcutaneous pulsatile glucocorticoid replacement therapy","volume":"81","author":"Russell","year":"2014","journal-title":"Clin. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coisb.2020.07.007","article-title":"Wearable technology and systems modeling for personalized chronotherapy","volume":"21","author":"Kim","year":"2020","journal-title":"Curr. Opin. Syst. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1210\/endrev\/bnaa002","article-title":"Dynamics of ACTH and Cortisol Secretion and Implications for Disease","volume":"41","author":"Lightman","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/03091900802185970","article-title":"Development of an automated blood sampling system for use in humans","volume":"33","author":"Henley","year":"2009","journal-title":"J. Med. Eng. Technol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105096","DOI":"10.1016\/j.psyneuen.2020.105096","article-title":"Glucocorticoid ultradian rhythmicity differentially regulates mood and resting state networks in the human brain: A randomised controlled clinical trial","volume":"124","author":"Kalafatakis","year":"2021","journal-title":"Psychoneuroendocrinology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1210\/jc.2011-2227","article-title":"Estimation of maximal cortisol secretion rate in healthy humans","volume":"97","author":"Dorin","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","unstructured":"Jambhekar, S.S., and Breen, P.J. (2012). Basic Pharmacokinetics, Pharmaceutical Press. [2nd ed.]."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1381\/096089206777346673","article-title":"Estimating blood volume in obese and morbidly obese patients","volume":"16","author":"Lemmens","year":"2006","journal-title":"Obes. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Thomsen, M., Hernandez-Garcia, A., Mathiesen, J., Poulsen, M., S\u00f8rensen, D.N., Tarnow, L., and Feidenhans\u2019l, R. (2014). Model study of the pressure build-up during subcutaneous injection. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104054"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1177\/193229681300700128","article-title":"Insulin depot formation in subcutaneoue tissue","volume":"7","author":"Roebrock","year":"2013","journal-title":"J. Diabetes. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13749","DOI":"10.1038\/s41598-018-32026-9","article-title":"Fluid absorption by skin tissue during intradermal injections through hollow microneedles","volume":"8","author":"Shrestha","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gradel, A.K.J., Porsgaard, T., Lykkesfeldt, J., Seested, T.T., Gram-Nielsen, S., Kristensen, N.R., and Refsgaard, H.H.F. (2018). Factors Affecting the Absorption of Subcutaneously Administered Insulin: Effect on Variability. J. Diabetes Res., 1205121.","DOI":"10.1155\/2018\/1205121"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/j.cmet.2017.05.004","article-title":"A Cell-Autonomous Mammalian 12 hr Clock Coordinates Metabolic and Stress Rhythms","volume":"25","author":"Zhu","year":"2017","journal-title":"Cell. Metab."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/6\/769\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:05:40Z","timestamp":1760162740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/6\/769"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,21]]},"references-count":28,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["pharmaceutics13060769"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13060769","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,21]]}}}