{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:52:35Z","timestamp":1791337955769,"version":"4.3.1"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007537","name":"Freie Universit\u00e4t Berlin","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007537","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Pharmacokinet Pharmacodyn"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5\u201310\u00a0mg hydrocortisone as granules, (ii) 20\u00a0mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10928-024-09934-7","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T16:02:34Z","timestamp":1720454554000},"page":"809-824","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy"],"prefix":"10.1007","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0758-5951","authenticated-orcid":false,"given":"Davide","family":"Bindellini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-607X","authenticated-orcid":false,"given":"Robin","family":"Michelet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4840-5704","authenticated-orcid":false,"given":"Linda B. S.","family":"Aulin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5463-8398","authenticated-orcid":false,"given":"Johanna","family":"Melin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-0577","authenticated-orcid":false,"given":"Uta","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1803-5589","authenticated-orcid":false,"given":"Oliver","family":"Blankenstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5249-3914","authenticated-orcid":false,"given":"Wilhelm","family":"Huisinga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2388-4753","authenticated-orcid":false,"given":"Martin J.","family":"Whitaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9222-9678","authenticated-orcid":false,"given":"Richard","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Kloft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"9934_CR1","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1016\/s0022-5347(17)42164-1","volume":"81","author":"S Pang","year":"1988","unstructured":"Pang S, Wallace MA, Hofman L et al (1988) Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 81:866\u2013874. https:\/\/doi.org\/10.1016\/s0022-5347(17)42164-1","journal-title":"Pediatrics"},{"key":"9934_CR2","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1016\/S0140-6736(05)66736-0","volume":"365","author":"DP Merke","year":"2005","unstructured":"Merke DP, Bornstein SR (2005) Congenital adrenal hyperplasia. Lancet 365:2125\u20132136. https:\/\/doi.org\/10.1016\/S0140-6736(05)66736-0","journal-title":"Lancet"},{"key":"9934_CR3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1210\/ENDREV\/BNAB016","volume":"43","author":"HLC van der Grinten","year":"2022","unstructured":"van der Grinten HLC, Speiser PW, Faisal Ahmed S et al (2022) Congenital adrenal hyperplasia-current insights in Pathophysiology, Diagnostics, and management. Endocr Rev 43:91\u2013159. https:\/\/doi.org\/10.1210\/ENDREV\/BNAB016","journal-title":"Endocr Rev"},{"key":"9934_CR4","doi-asserted-by":"publisher","first-page":"432","DOI":"10.3389\/FENDO.2019.00432","volume":"10","author":"D Pignatelli","year":"2019","unstructured":"Pignatelli D, Carvalho BL, Palmeiro A et al (2019) The complexities in genotyping of congenital adrenal hyperplasia: 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne) 10:432. https:\/\/doi.org\/10.3389\/FENDO.2019.00432","journal-title":"Front Endocrinol (Lausanne)"},{"key":"9934_CR5","doi-asserted-by":"publisher","first-page":"2611","DOI":"10.1073\/PNAS.1300057110\/SUPPL_FILE\/PNAS.201300057SI.PDF","volume":"110","author":"MI New","year":"2013","unstructured":"New MI, Abraham M, Gonzalez B et al (2013) Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A 110:2611\u20132616. https:\/\/doi.org\/10.1073\/PNAS.1300057110\/SUPPL_FILE\/PNAS.201300057SI.PDF","journal-title":"Proc Natl Acad Sci U S A"},{"key":"9934_CR6","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/HUMU.1380030408","volume":"3","author":"PC White","year":"1994","unstructured":"White PC, Tusie-Luna M, \u2010T, New MI, Speiser PW (1994) Mutations in steroid 21-hydroxylase (CYP21). Hum Mutat 3:373\u2013378. https:\/\/doi.org\/10.1002\/HUMU.1380030408","journal-title":"Hum Mutat"},{"key":"9934_CR7","doi-asserted-by":"publisher","first-page":"77","DOI":"10.20945\/2359-3997000000438","volume":"66","author":"CE Kater","year":"2022","unstructured":"Kater CE, Giorgi RB, Costa-Barbosa FA (2022) Classic and current concepts in adrenal steroidogenesis: a reappraisal. Arch Endocrinol Metab 66:77. https:\/\/doi.org\/10.20945\/2359-3997000000438","journal-title":"Arch Endocrinol Metab"},{"key":"9934_CR8","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1210\/JCEM.84.5.5631","volume":"84","author":"SR Bornstein","year":"1999","unstructured":"Bornstein SR, Chrousos GP (1999) Clinical review 104: Adrenocorticotropin (ACTH)- and non-ACTH-mediated regulation of the adrenal cortex: neural and immune inputs. J Clin Endocrinol Metab 84:1729\u20131736. https:\/\/doi.org\/10.1210\/JCEM.84.5.5631","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR9","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1159\/000181089","volume":"31","author":"MA Smith","year":"1989","unstructured":"Smith MA, Kling MA, Whitfield HJ et al (1989) Corticotropin-releasing hormone: from endocrinology to psychobiology. Horm Res 31:66\u201371. https:\/\/doi.org\/10.1159\/000181089","journal-title":"Horm Res"},{"key":"9934_CR10","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1002\/CPHY.C140003","volume":"4","author":"F Spiga","year":"2014","unstructured":"Spiga F, Walker JJ, Terry JR, Lightman SL (2014) HPA axis-rhythms. Compr Physiol 4:1273\u20131298. https:\/\/doi.org\/10.1002\/CPHY.C140003","journal-title":"Compr Physiol"},{"key":"9934_CR11","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1111\/NYAS.12464","volume":"1318","author":"NC Nicolaides","year":"2014","unstructured":"Nicolaides NC, Charmandari E, Chrousos GP, Kino T (2014) Circadian endocrine rhythms: the hypothalamic-pituitary-adrenal axis and its actions. Ann N Y Acad Sci 1318:71\u201380. https:\/\/doi.org\/10.1111\/NYAS.12464","journal-title":"Ann N Y Acad Sci"},{"key":"9934_CR12","doi-asserted-by":"publisher","first-page":"4043","DOI":"10.1210\/JC.2018-01865","volume":"103","author":"PW Speiser","year":"2018","unstructured":"Speiser PW, Arlt W, Auchus RJ et al (2018) Congenital adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency: an endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 103:4043\u20134088. https:\/\/doi.org\/10.1210\/JC.2018-01865","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1111\/J.1365-2265.2004.02106.X","volume":"61","author":"PM Mah","year":"2004","unstructured":"Mah PM, Jenkins RC, Rostami-Hodjegan A et al (2004) Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol (Oxf) 61:367\u2013375. https:\/\/doi.org\/10.1111\/J.1365-2265.2004.02106.X","journal-title":"Clin Endocrinol (Oxf)"},{"key":"9934_CR14","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1530\/EJE-20-0231","volume":"183","author":"R Michelet","year":"2020","unstructured":"Michelet R, Melin J, Parra-Guillen ZP et al (2020) Paediatric population pharmacokinetic modelling to assess hydrocortisone replacement dosing regimens in young children. Eur J Endocrinol 183:357\u2013368. https:\/\/doi.org\/10.1530\/EJE-20-0231","journal-title":"Eur J Endocrinol"},{"key":"9934_CR15","doi-asserted-by":"publisher","first-page":"819590","DOI":"10.3389\/FPHAR.2022.819590\/FULL","volume":"13","author":"V Stachanow","year":"2022","unstructured":"Stachanow V, Neumann U, Blankenstein O et al (2022) Exploring dried blood spot cortisol concentrations as an Alternative for Monitoring Pediatric adrenal insufficiency patients: a model-based analysis. Front Pharmacol 13:819590. https:\/\/doi.org\/10.3389\/FPHAR.2022.819590\/FULL","journal-title":"Front Pharmacol"},{"key":"9934_CR16","doi-asserted-by":"publisher","unstructured":"Janmahasatian S, Duffull SB, Ash S et al (2012) Quantification of Lean Bodyweight. Clinical Pharmacokinetics 2005 44:10 44:1051\u20131065. https:\/\/doi.org\/10.2165\/00003088-200544100-00004","DOI":"10.2165\/00003088-200544100-00004"},{"key":"9934_CR17","doi-asserted-by":"publisher","unstructured":"Rozenveld E, Punt N, van Faassen M et al (2022) Pharmacokinetic modeling of hydrocortisone by including protein binding to corticosteroid-binding globulin. https:\/\/doi.org\/10.3390\/PHARMACEUTICS14061161. Pharmaceutics 14:","DOI":"10.3390\/PHARMACEUTICS14061161"},{"key":"9934_CR18","doi-asserted-by":"publisher","unstructured":"Bonner JJ, Burt H, Johnson TN et al (2021) Development and verification of an endogenous PBPK model to inform hydrocortisone replacement dosing in children and adults with cortisol deficiency. Eur J Pharm Sci 165. https:\/\/doi.org\/10.1016\/J.EJPS.2021.105913","DOI":"10.1016\/J.EJPS.2021.105913"},{"key":"9934_CR19","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/CEN.13969","volume":"91","author":"J Melin","year":"2019","unstructured":"Melin J, Hartung N, Parra-Guillen ZP et al (2019) The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing. Clin Endocrinol (Oxf) 91:33\u201340. https:\/\/doi.org\/10.1111\/CEN.13969","journal-title":"Clin Endocrinol (Oxf)"},{"key":"9934_CR20","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1007\/S40262-017-0575-8","volume":"57","author":"J Melin","year":"2018","unstructured":"Melin J, Parra-Guillen ZP, Hartung N et al (2018) Predicting Cortisol exposure from Paediatric Hydrocortisone Formulation using a semi-mechanistic pharmacokinetic model established in healthy adults. Clin Pharmacokinet 57:515\u2013527. https:\/\/doi.org\/10.1007\/S40262-017-0575-8","journal-title":"Clin Pharmacokinet"},{"key":"9934_CR21","doi-asserted-by":"publisher","first-page":"464","DOI":"10.3390\/PH16030464\/S1","volume":"16","author":"V Stachanow","year":"2023","unstructured":"Stachanow V, Neumann U, Blankenstein O et al (2023) Model-informed Target Morning 17\u03b1-Hydroxyprogesterone concentrations in dried blood spots for Pediatric congenital adrenal hyperplasia patients. Pharmaceuticals 16:464. https:\/\/doi.org\/10.3390\/PH16030464\/S1","journal-title":"Pharmaceuticals"},{"key":"9934_CR22","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1128\/AAC.48.5.1441-1453.2004","volume":"48","author":"M M\u00fcller","year":"2004","unstructured":"M\u00fcller M, Pe\u00f1a A, dela, Derendorf H (2004) Issues in Pharmacokinetics and Pharmacodynamics of Anti-infective agents: distribution in tissue. Antimicrob Agents Chemother 48:1441. https:\/\/doi.org\/10.1128\/AAC.48.5.1441-1453.2004","journal-title":"Antimicrob Agents Chemother"},{"key":"9934_CR23","doi-asserted-by":"publisher","first-page":"3925","DOI":"10.1074\/JBC.M805081200","volume":"284","author":"LJ Mullins","year":"2009","unstructured":"Mullins LJ, Peter A, Wrobel N et al (2009) Cyp11b1 null mouse, a model of congenital adrenal hyperplasia. J Biol Chem 284:3925\u20133934. https:\/\/doi.org\/10.1074\/JBC.M805081200","journal-title":"J Biol Chem"},{"key":"9934_CR24","unstructured":"Study Record | ClinicalTrials.gov https:\/\/clinicaltrials.gov\/study\/NCT02777268. Accessed 25 Sep 2023"},{"key":"9934_CR25","unstructured":"An Investigational Study of Hydrocortisone - Full Text View - ClinicalTrials.gov. https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT01960530. Accessed 25 Sep 2023"},{"key":"9934_CR26","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1210\/JC.2015-3694","volume":"101","author":"M Debono","year":"2016","unstructured":"Debono M, Harrison RF, Whitaker MJ et al (2016) Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone. J Clin Endocrinol Metab 101:1469\u20131477. https:\/\/doi.org\/10.1210\/JC.2015-3694","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR27","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/S10928-007-9066-0","volume":"34","author":"RM Savic","year":"2007","unstructured":"Savic RM, Jonker DM, Kerbusch T, Karlsson MO (2007) Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 34:711\u2013726. https:\/\/doi.org\/10.1007\/S10928-007-9066-0","journal-title":"J Pharmacokinet Pharmacodyn"},{"key":"9934_CR28","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1210\/JCEM.87.1.8158","volume":"87","author":"R Pasquali","year":"2002","unstructured":"Pasquali R, Ambrosi B, Armanini D et al (2002) Cortisol and ACTH response to oral dexamethasone in obesity and effects of Sex, Body Fat Distribution, and dexamethasone concentrations: a dose-response study. J Clin Endocrinol Metab 87:166\u2013175. https:\/\/doi.org\/10.1210\/JCEM.87.1.8158","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR29","doi-asserted-by":"publisher","unstructured":"Wollmer E, Karkossa F, Freerks L et al (2020) A Biopredictive in Vitro Approach for assessing compatibility of a Novel Pediatric Hydrocortisone Drug Product within Common Pediatric Dosing vehicles. Pharm Res 37. https:\/\/doi.org\/10.1007\/S11095-020-02912-X","DOI":"10.1007\/S11095-020-02912-X"},{"key":"9934_CR30","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1210\/JC.2015-1700","volume":"101","author":"NS Ospina","year":"2016","unstructured":"Ospina NS, Nofal A, Al, Bancos I et al (2016) ACTH Stimulation tests for the diagnosis of adrenal insufficiency: systematic review and Meta-analysis. J Clin Endocrinol Metab 101:427\u2013434. https:\/\/doi.org\/10.1210\/JC.2015-1700","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR31","doi-asserted-by":"publisher","first-page":"20916","DOI":"10.1016\/S0021-9258(17)45304-X","volume":"265","author":"MT Tusie-Luna","year":"1990","unstructured":"Tusie-Luna MT, Traktman P, White PC (1990) Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem 265:20916\u201320922. https:\/\/doi.org\/10.1016\/S0021-9258(17)45304-X","journal-title":"J Biol Chem"},{"key":"9934_CR32","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1210\/MEND.6.8.1406709","volume":"6","author":"A Helmberg","year":"1992","unstructured":"Helmberg A, Tusie-Luna MT, Tabarelli M et al (1992) R339H and P453S: CYP21 mutations associated with nonclassic steroid 21-hydroxylase deficiency that are not apparent gene conversions. Mol Endocrinol 6:1318\u20131322. https:\/\/doi.org\/10.1210\/MEND.6.8.1406709","journal-title":"Mol Endocrinol"},{"key":"9934_CR33","doi-asserted-by":"publisher","first-page":"E2063","DOI":"10.1210\/CLINEM\/DGAB051","volume":"106","author":"DP Merke","year":"2021","unstructured":"Merke DP, Mallappa A, Arlt W et al (2021) Modified-release hydrocortisone in congenital adrenal Hyperplasia. J Clin Endocrinol Metab 106:E2063\u2013E2077. https:\/\/doi.org\/10.1210\/CLINEM\/DGAB051","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR34","doi-asserted-by":"publisher","unstructured":"Veldhuis JD, Iranmanesh A, Lizarralde G, Johnson ML (1989) Amplitude modulation of a burstlike mode of cortisol secretion subserves the circadian glucocorticoid rhythm. Am J Physiol 257. https:\/\/doi.org\/10.1152\/AJPENDO.1989.257.1.E6","DOI":"10.1152\/AJPENDO.1989.257.1.E6"},{"key":"9934_CR35","doi-asserted-by":"publisher","first-page":"R73","DOI":"10.1530\/EJE-18-0853","volume":"180","author":"K Kalafatakis","year":"2019","unstructured":"Kalafatakis K, Russell GM, Lightman SL (2019) MECHANISMS IN ENDOCRINOLOGY: does circadian and ultradian glucocorticoid exposure affect the brain? Eur J Endocrinol 180:R73\u2013R89. https:\/\/doi.org\/10.1530\/EJE-18-0853","journal-title":"Eur J Endocrinol"},{"key":"9934_CR36","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/J.ANDO.2018.03.003","volume":"79","author":"BP Flynn","year":"2018","unstructured":"Flynn BP, Conway-Campbell BL, Lightman SL (2018) The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology. Ann Endocrinol (Paris) 79:112\u2013114. https:\/\/doi.org\/10.1016\/J.ANDO.2018.03.003","journal-title":"Ann Endocrinol (Paris)"},{"key":"9934_CR37","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1111\/CEN.13999","volume":"91","author":"S Choudhury","year":"2019","unstructured":"Choudhury S, Lightman S, Meeran K (2019) Improving glucocorticoid replacement profiles in adrenal insufficiency. Clin Endocrinol (Oxf) 91:367\u2013371. https:\/\/doi.org\/10.1111\/CEN.13999","journal-title":"Clin Endocrinol (Oxf)"},{"key":"9934_CR38","doi-asserted-by":"publisher","first-page":"1627","DOI":"10.1098\/RSPB.2009.2148","volume":"277","author":"JJ Walker","year":"2010","unstructured":"Walker JJ, Terry JR, Lightman SL (2010) Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis. Proc Biol Sci 277:1627\u20131633. https:\/\/doi.org\/10.1098\/RSPB.2009.2148","journal-title":"Proc Biol Sci"},{"key":"9934_CR39","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1111\/BCP.14470","volume":"87","author":"M Al-Kofahi","year":"2021","unstructured":"Al-Kofahi M, Ahmed MA, Jaber MM et al (2021) An integrated PK-PD model for cortisol and the 17-hydroxyprogesterone and androstenedione biomarkers in children with congenital adrenal hyperplasia. Br J Clin Pharmacol 87:1098\u20131110. https:\/\/doi.org\/10.1111\/BCP.14470","journal-title":"Br J Clin Pharmacol"},{"key":"9934_CR40","doi-asserted-by":"publisher","first-page":"e1729","DOI":"10.1210\/CLINEM\/DGAA071","volume":"105","author":"J Melin","year":"2020","unstructured":"Melin J, Parra-Guillen ZP, Michelet R et al (2020) Pharmacokinetic\/Pharmacodynamic Evaluation of Hydrocortisone Therapy in Pediatric patients with congenital adrenal Hyperplasia. J Clin Endocrinol Metab 105:e1729\u2013e1740. https:\/\/doi.org\/10.1210\/CLINEM\/DGAA071","journal-title":"J Clin Endocrinol Metab"},{"key":"9934_CR41","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1111\/J.1365-2125.2007.02867.X","volume":"64","author":"A L\u00f6nnebo","year":"2007","unstructured":"L\u00f6nnebo A, Grahn\u00e9n A, Karlsson MO (2007) An integrated model for the effect of budesonide on ACTH and cortisol in healthy volunteers. Br J Clin Pharmacol 64:125. https:\/\/doi.org\/10.1111\/J.1365-2125.2007.02867.X","journal-title":"Br J Clin Pharmacol"},{"key":"9934_CR42","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1210\/JENDSO\/BVAC173","volume":"7","author":"RI Dorin","year":"2022","unstructured":"Dorin RI, Urban FK, Perogamvros I, Qualls CR (2022) Four-compartment diffusion model of Cortisol Disposition: comparison with 3 alternative models in current clinical use. J Endocr Soc 7:1\u201313. https:\/\/doi.org\/10.1210\/JENDSO\/BVAC173","journal-title":"J Endocr Soc"},{"key":"9934_CR43","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1210\/ENDO.142.4.8114","volume":"142","author":"JR Seckl","year":"2001","unstructured":"Seckl JR, Walker BR (2001) Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology 142:1371\u20131376. https:\/\/doi.org\/10.1210\/ENDO.142.4.8114","journal-title":"Endocrinology"},{"key":"9934_CR44","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1002\/CPHY.C150015","volume":"6","author":"JP Herman","year":"2016","unstructured":"Herman JP, McKlveen JM, Ghosal S et al (2016) Regulation of the hypothalamic-pituitary-adrenocortical stress response. Compr Physiol 6:603\u2013621. https:\/\/doi.org\/10.1002\/CPHY.C150015","journal-title":"Compr Physiol"},{"key":"9934_CR45","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/S0022-3999(02)00429-4","volume":"53","author":"C Tsigos","year":"2002","unstructured":"Tsigos C, Chrousos GP (2002) Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865\u2013871. https:\/\/doi.org\/10.1016\/S0022-3999(02)00429-4","journal-title":"J Psychosom Res"},{"key":"9934_CR46","doi-asserted-by":"publisher","unstructured":"Michelet R, Bindellini D, Melin J et al (2023) Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach. Front Pharmacol 13. https:\/\/doi.org\/10.3389\/FPHAR.2022.1090554","DOI":"10.3389\/FPHAR.2022.1090554"},{"key":"9934_CR47","doi-asserted-by":"publisher","first-page":"L29","DOI":"10.1530\/EJE-20-1047","volume":"183","author":"R Michelet","year":"2020","unstructured":"Michelet R, Melin J, Parra-Guillen ZP et al (2020) Response to \u2018Hydrocortisone suspension formulations are not necessarily the same in the treatment of children with congenital adrenal hyperplasia\u2019. Eur J Endocrinol 183:L29\u2013L30. https:\/\/doi.org\/10.1530\/EJE-20-1047","journal-title":"Eur J Endocrinol"}],"container-title":["Journal of Pharmacokinetics and Pharmacodynamics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10928-024-09934-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10928-024-09934-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10928-024-09934-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,20]],"date-time":"2024-11-20T12:05:24Z","timestamp":1732104324000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10928-024-09934-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,8]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["9934"],"URL":"https:\/\/doi.org\/10.1007\/s10928-024-09934-7","relation":{},"ISSN":["1567-567X","1573-8744"],"issn-type":[{"value":"1567-567X","type":"print"},{"value":"1573-8744","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,8]]},"assertion":[{"value":"21 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"D.B., R.M., L.A. and M.J.W. have no conflict of interest. U.N. received a consultant and presentation fee from Diurnal Ltd., O.B. received a presentation fee from Diurnal Ltd., R.R. is a consultant to Neurocrine (Diurnal Ltd.). C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. K.G., Astra Zeneca, Boehringer Ingelheim Pharma GmbH & Co. K.G., F. Hoffmann-La Roche Ltd., Merck KGaA, Novo Nordisk, and Sanofi) for the PharMetrX PhD program. C.K. reports an additional grant from the Innovative Medicines Initiative-Joint Undertaking (\u2018DDMoRe\u2019), grants from the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within in the Horizon 2020 framework programme (\u201cFAIR\u201d), all outside the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}