Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults
Abstract
Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort® oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency.Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort® or 20 mg of Infacort®/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model.Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline cort,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing <20 kg.Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing <20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.
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Both ABS1 and ABS2 absorption models performed better than the original saturable absorption model based on goodness-of-fit plots.
“Both approaches generated conceptually similar models with plausible parameter estimates and both performed better than the original saturable absorption model [20], based on GOF plots (Fig. 3).”
From A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy (2024) · cites this paper as [20]
Non-linear mixed-effects approaches predicted that no significant maturation of cortisol binding globulin takes place over the entire pediatric age range, while a physiologically-based pharmacokinetic approach showed an increase in cortisol binding globulin concentration from birth to adulthood.
“For the maturation of CBG, NLME approaches predicted that no significant maturation takes place over the entire pediatric age range ( Melin et al., 2017 ; Melin et al., 2019 ) while a PBPK approach showed an increase in CBG concentration from birth to adulthood ( Bonner et al., 2021 ).”
From Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach (2023) · cites this paper as Melin et al., 2017
The available clinical data was too sparse to quantify an impact of age on the pharmacokinetic parameters after taking body weight into consideration.
“However, the available clinical data was too sparse to quantify an impact of age on the PK parameters after taking body weight into consideration.”
From Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach (2023) · cites this paper as Melin et al., 2017
Cites
Cook, R. J., Dickens, B. M., & Fathalla, M. F. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199241323.003.0025 · Cited by 10,813 · see citing works
(2001) · Journal of obstetrics and gynaecology research · doi:10.1111/j.1447-0756.2001.tb01222.x · Cited by 3,515 · see citing works
Bornstein, S. R., Allolio, B., Arlt, W., Barthel, A., Don-Wauchope, A., Hammer, G. D., Husebye, E. S., Merke, D. P., Murad, M. H., Stratakis, C. A., et al. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-1710 · Cited by 1,769 · see citing works
Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2631 · Cited by 1,484 · cited 1× · see citing works
“5–5 mg) as crushed tablets suspended inwater [5, 6].”
BackgroundLindbom, L., Pihlgren, P., & Jonsson, E. N. (2005) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2005.04.005 · Cited by 1,137 · see citing works
Changes in plasma protein binding have little clinical relevance
Benet, L. Z., & Hoener, B. (2002) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2002.121829 · Cited by 825 · see citing works
Westphal, U. (1963) · doi:10.21236/ad0423987 · Cited by 675 · see citing works
Westphal, U. (1971) · Monographs on endocrinology · doi:10.1007/978-3-642-46262-7 · Cited by 415 · see citing works
Lindbom, L., Pihlgren, P., & Jonsson, E. N. (2005) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2005.10.001 · Cited by 321 · see citing works
Coolens, J.-L., Van Baelen, H., & Heyns, W. (1987) · Journal of Steroid Biochemistry · doi:10.1016/0022-4731(87)90071-9 · Cited by 290 · see citing works
Mah, P. M., Jenkins, R. C., Rostami‐Hodjegan, A., Newell‐Price, J., Doane, A., Ibbotson, V., Tucker, G. T., & Ross, R. J. (2004) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2004.02106.x · Cited by 243 · see citing works
Self-citationKnutsson, U., Dahlgren, J., Marcus, C., Rosberg, S., Brönnegård, M., Stierna, P., & Albertsson-Wikland, K. G. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3769 · Cited by 209 · see citing works
Pharmacokinetics and Oral Bioavailability of Hydrocortisone
Derendorf, H., Möllmann, H., Barth, J., Möllmann, C., Tunn, S., & Krieg, M. (1991) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1991.tb01906.x · Cited by 168 · see citing works
Chronopharmacology of glucocorticoids
Scherholz, M. L., Schlesinger, N., & Androulakis, I. P. (2019) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2019.02.004 · Cited by 145 · see citing works
Knutsson, U. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.82.2.536 · Cited by 140 · see citing works
Debono, M., Harrison, R. F., Whitaker, M. J., Eckland, D., Arlt, W., Keevil, B. G., & Ross, R. J. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-3694 · Cited by 128 · see citing works
Self-citationWestphal, U. (1967) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(67)90390-6 · Cited by 124 · see citing works
Charmandari, E., Johnston, A. E., Brook, C. G. D., & Hindmarsh, P. C. (2001) · Journal of Endocrinology · doi:10.1677/joe.0.1690065 · Cited by 104 · see citing works
Approaches to handling pharmacodynamic baseline responses
Dansirikul, C., Silber, H. E., & Karlsson, M. O. (2008) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-008-9088-2 · Cited by 80 · see citing works
Merke, D. P., Cho, D., Anton Calis, K., Keil, M. F., & Chrousos, G. P. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.1.7275 · Cited by 65 · see citing works
Simon, N., Castinetti, F., Ouliac, F., Lesavre, N., Brue, T., & Oliver, C. (2010) · Clinical Pharmacokinetics · doi:10.2165/11531290-000000000-00000 · Cited by 61 · 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-citationCortisol Binding to Proteins in Plasma in the Human Neonate and Infant
Hadjian, A. J., Chedin, M., Cochet, C., & CHAMBAZ, E. M. (1975) · Pediatric Research · doi:10.1203/00006450-197501000-00008 · Cited by 48 · see citing works
Whitaker, M. J., Spielmann, S., Digweed, D., Huatan, H., Eckland, D., Johnson, T. N., Tucker, G., Krude, H., Blankenstein, O., & Ross, R. J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4060 · Cited by 48 · see citing works
Self-citationToothaker, R. D., & Welling, P. G. (1982) · Journal of Pharmacokinetics and Biopharmaceutics · doi:10.1007/bf01062332 · Cited by 46 · see citing works
Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients
Hoshiro, M., Ohno, Y., Masaki, H., et al. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02412.x · Cited by 44 · see citing works
Effect of Dose Size on the Pharmacokinetics of Oral Hydrocortisone Suspension
Roger, D., Craig, W. A., & Welling, P. G. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600711029 · Cited by 38 · see citing works
Lewis, J. G., Lewis, M. G., & Elder, P. A. (2003) · Clinica Chimica Acta · doi:10.1016/s0009-8981(02)00417-5 · Cited by 38 · see citing works
Toothaker, R. D., Sundaresan, G. M., Hunt, J. P., Goehl, T. J., Rotenberg, K. S., Prasad, V. K., Craig, W. A., & Welling, P. G. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710522 · Cited by 37 · see citing works
Plasma Variation of Corticosteroid-binding Globulin and Sex Hormone-binding Globulin
Lewis, J. G., Möpert, B., Shand, B. I., Doogue, M. P., Soule, S. G., Frampton, C. M., & Elder, P. A. (2006) · Hormone and Metabolic Research · doi:10.1055/s-2006-925338 · Cited by 33 · 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
Picard‐Hagen, N., Gayrard, V., Alvinerie, M., Smeyers, H., Ricou, R., Bousquet‐mélou, A., & Toutain, P. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.5.e946 · Cited by 29 · see citing works
Rogers, S. L., Hughes, B. A., Jones, C. A., Freedman, L., Smart, K., Taylor, N., Stewart, P. M., Shackleton, C. H. L., Krone, N. P., Blissett, J., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3254 · Cited by 25 · see citing works
Lennernäs, H., Skrtic, S., & Johannsson, G. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.6.749 · Cited by 23 · see citing works
Wright, D. H., Stone, J. A., Crumley, T. M., Wenning, L. A., Zheng, W., Yan, K. X., Yang, A. Y., Sun, L. Z., Cilissen, C., Ramael, S., et al. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12131 · Cited by 18 · see citing works
Choi, H., Park, S. Y., Park, S. Y., et al. (2019) · Korean Journal of Anesthesiology · doi:10.4097/kja.d.18.00238 · Cited by 9 · see citing works
Chung, T., Gunganah, K., Monson, J. P., & Drake, W. M. (2015) · Clinical Endocrinology · doi:10.1111/cen.12982 · Cited by 7 · 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
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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
Self-citationPorter, 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-citationMichelet, R., Bindellini, D., Melin, J., Neumann, U., Blankenstein, O., Huisinga, W., Johnson, T. N., Whitaker, M. J., Ross, R., & Kloft, C. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1090554 · Cited by 5 · see citing works
Self-citationBindellini, D., Michelet, R., Aulin, L. B. S., Melin, J., Neumann, U., Blankenstein, O., Huisinga, W., Whitaker, M. J., Ross, R., & Kloft, C. (2024) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-024-09934-7 · Cited by 4 · see citing works
“Both approaches generated conceptually similar models with plausible parameter estimates and both performed better than the original saturable absorption model [ 20], based on GOF plots (Fig.”
InfluentialSelf-citation
- Authors
- Melin, J., Parra-Guillen, Z. P., Hartung, N., Huisinga, W., Ross, R. J., Whitaker, M. J., & Kloft, C.
- Affiliations
- Freie Universität Berlin (DE)
- University of Potsdam (DE)
- University of Sheffield (GB)
- Diurnal (United Kingdom) (GB)
- Corresponding author
- Kloft, Charlotte
- ORCID
- Venue
- Clinical Pharmacokinetics
- Published
- 2017-07-31
- Volume
- 57
- Issue
- 4
- Pages
- 515-527
- ISSN
- 0312-5963 (ISSN-L)
- 1179-1926
- OpenAlex
- W2740890599
- Cited by
- 17
- References
- 39
- Citations by year
- 2025: 1 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 1
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacokinetics (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- publish.UP (University of Potsdam) (submittedVersion)
- Funders
- European Commission FP7 Grant (281654 TAIN)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
- Keywords
- cortisol, adrenal insufficiency, population pharmacokinetic model, semi-mechanistic model, protein binding, dexamethasone suppression, saturable absorption, cortisol-binding protein, dose prediction
- MeSH terms
- Administration, Oral, Adrenal Insufficiency, Adult, Age Factors, Child, Preschool, Computer Simulation, Drug Compounding, Glucocorticoids, Humans, Hydrocortisone, Infant, Infant, Newborn, Middle Aged, Models, Biological, Protein Binding, Randomized Controlled Trials as Topic, Hormone Replacement Therapy, Drug Dosage Calculations, Young Adult, Administration, Intravenous
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