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Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults

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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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References

  1. Bornstein SR, Allolio B, Arlt W, Barthel A, Don-Wauchope A, Hammer GD, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:364–89.

    Article  CAS  PubMed  Google Scholar 

  2. Porter J, Blair J, Ross RJ. Is physiological glucocorticoid replacement important in children? Arch Dis Child. 2017;102:199–205.

    Article  PubMed  Google Scholar 

  3. Toothaker RD, Sundaresan GM, Hunt JP, Goehl TJ, Rotenberg KS, Prasad VK, et al. Oral hydrocortisone pharmacokinetics: a comparison of fluorescence and ultraviolet high-pressure liquid. J Pharm Sci. 1982;71:573–6.

    Article  CAS  PubMed  Google Scholar 

  4. Derendorf H, Mollmann H, Barth J, Mollmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharm. 1991;31:473–6.

    Article  CAS  Google Scholar 

  5. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:4133–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Whitaker MJ, Spielmann S, Digweed D, Huatan H, Eckland D, Johnson TN, et al. Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency. J Clin Endocrinol Metab. 2015;100:1681–8.

    Article  CAS  PubMed  Google Scholar 

  7. Kauzor D, Spielmann S, Brosig H, Ross R, Blankenstein O, Kloft C. Medication safety study investigating hydrocortisone individually and extemporaneously compounded capsules for paediatric use in CAH [abstract no. P825]. 16th European Congress of Endocrinology, 2014. http://www.endocrine-abstracts.org/ea/0035/ea0035P825.htm. Accessed 25 Jun 2017.

  8. Merke DP, Cho D, Calis KA, Keil MF, Chrousos GP. Hydrocortisone suspension and hydrocortisone tablets are not bioequivalent in the treatment of children with congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86:441–5.

    Article  CAS  PubMed  Google Scholar 

  9. Toothaker RD, Welling PG. Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression. J Pharmacokinet Biopharm. 1982;10:147–56.

    Article  CAS  PubMed  Google Scholar 

  10. Lentjes EGWM. Romijn FHTPM. Temperature-dependent cortisol distribution among the blood compartments in man. J Clin Endocrinol Metab. 1999;84:682–7.

    Article  CAS  PubMed  Google Scholar 

  11. Toothaker RD, Craig WA, Welling PG. Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sci. 1982;71:1182–5.

    Article  CAS  PubMed  Google Scholar 

  12. Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, et al. Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol. 2004;61:367–75.

    Article  CAS  Google Scholar 

  13. Simon N, Castinetti F, Ouliac F, Lesavre N, Brue T, Oliver C. Pharmacokinetic evidence for suboptimal treatment of adrenal insufficiency with currently available hydrocortisone tablets. Clin Pharmacokinet. 2010;49:455–63.

    Article  CAS  PubMed  Google Scholar 

  14. Hoshiro M, Ohno Y, Masaki H, Iwase H, Aoki N. Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients. Clin Endocrinol. 2006;64:37–45.

    Article  CAS  Google Scholar 

  15. Debono M, Harrison RF, Whitaker MJ, Eckland D, Arlt W, Keevil BG, et al. Salivary cortisone reflects cortisol exposure under physiological conditions and after hydrocortisone. J Clin Endocrinol Metab. 2016;101:1469–77.

    Article  CAS  PubMed  Google Scholar 

  16. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.

    Article  Google Scholar 

  17. Association of the British Pharmaceutical Industry. Guidelines for phase 1 clinical trials (2012 edition). http://www.abpi.org.uk/our-work/library/guidelines/Pages/phase-1-trials-2012.aspx. Accessed 18 Nov 2016.

  18. International Council for Harmonisation of Technical Requirements for Human Use. Guideline for good clinical practice E6(R1). http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/good-clinical-practice.html. Accessed 18 Nov 2016.

  19. Lewis JG, Lewis MG, Elder PA. An enzyme-linked immunosorbent assay for corticosteroid-binding globulin using monoclonal and polyclonal antibodies: decline in CBG following synthetic ACTH. Clin Chim Acta. 2003;328:121–8.

    Article  CAS  PubMed  Google Scholar 

  20. Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2009). Ellicott City: Icon Development Solutions; 2009.

  21. Lindbom L, Pihlgren P, Jonsson EN, Jonsson N. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79:241–57.

    Article  PubMed  Google Scholar 

  22. Dansirikul C, Silber HE, Karlsson MO. Approaches to handling pharmacodynamic baseline responses. J Pharmacokinet Pharmacodyn. 2008;35:269–83.

    Article  CAS  PubMed  Google Scholar 

  23. Keizer R, Pastoor D, Savic R. New open source R libraries for simulation and visualization: “PKPDsim” and “vpc” 2015. http://www.page-meeting.eu/pdf_assets/1215-Page_Keizer_2015_pkpdsim_vpc.pdf. Accessed 5 Oct 2016.

  24. R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2016. ISBN 3-900051-07-0. http://www.R-project.org. Accessed 15 June 2016.

  25. Knutsson U, Dahlgren J, Marcus C, Rosberg S, Brönnegård M, Stierna P, et al. Circadian cortisol rhythms in healthy boys and girls: relationship with age, growth, body composition, and pubertal development. J Clin Endocrinol Metab. 1997;82:536–40.

    CAS  PubMed  Google Scholar 

  26. Rohatgi A. WebPlotDigitizer. http://arohatgi.info/WebPlotDigitizer. Accessed 5 Oct 2016.

  27. Wright DH, Stone JA, Crumley TM, Wenning L, Zheng W, Yan K, et al. Pharmacokinetic-pharmacodynamic studies of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor MK-0916 in healthy subjects. Br J Clin Pharmacol. 2013;76:917–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Picard-Hagen N, Gayrard V, Alvinerie M, Smeyers H, Ricou R, Bousquet-Melou A, et al. A nonlabeled method to evaluate cortisol production rate by modeling plasma CBG-free cortisol disposition. Am J Physiol Endocrinol Metab. 2001;281:E946–56.

    Article  CAS  PubMed  Google Scholar 

  29. Charmandari E, Johnston A, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol. 2001;169:65–70.

    Article  CAS  PubMed  Google Scholar 

  30. Lennernäs H, Skrtic S, Johannsson G. Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors. Expert Opin Drug Metab Toxicol. 2008;4:749–58.

    Article  PubMed  Google Scholar 

  31. Westphal U. Steroid-protein interactions. In: Gross F, Labhart A, Mann T, Samuels L (eds.) 1st edn. New York: Springer; 1971.

  32. Westphal U. Steroid-protein interactions XIII. Concentrations and binding affinities of corticosteroid-binding globulins in sera of man, monkey, rat, rabbit and guinea pig. Arch Biochem Biophys. 1967;118:556–67.

    Article  CAS  PubMed  Google Scholar 

  33. Coolens J-L, Baelen HVAN, Heyns W. Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem. 1987;26:197–202.

    Article  CAS  PubMed  Google Scholar 

  34. Lewis JG, Möpert B, Shand BI, Doogue MP, Soule SG, Frampton CM, et al. Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin. Horm Metab Res. 2006;38:241–5.

    Article  CAS  PubMed  Google Scholar 

  35. Chung TT, Gunganah K, Monson JP, Drake WM. Circadian variation in serum cortisol during hydrocortisone replacement is not attributable to changes in cortisol-binding globulin concentrations. Clin Endocrinol. 2016;84:496–500.

    Article  CAS  Google Scholar 

  36. Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115–21.

    Article  CAS  PubMed  Google Scholar 

  37. Hadjian AJ, Chedin M, Cochet C, Chambaz EM. Cortisol binding to proteins in plasma in the human neonate and infant. Pediatr Res. 1975;9:40–5.

    Article  CAS  Google Scholar 

  38. Rogers SL, Hughes BA, Jones CA, Freedman L, Smart K, Taylor N, et al. Diminished 11β-hydroxysteroid dehydrogenase type 2 activity is associated with decreased weight and weight gain across the first year of life. J Clin Endocrinol Metab. 2014;99:E821–31.

    Article  CAS  PubMed  Google Scholar 

  39. World Health Organisation. WHO child growth standards. 2006. http://www.who.int/childgrowth/standards/Technical_report.pdf. Accessed 19 Apr 2017.

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Acknowledgements

The authors would like to thank the high-performance computing service of ZEDAT, Freie Universitaet Berlin, for computing time. In addition, the authors would like to thank Trevor Johnson and Dena Digweed for valuable support. Parts of the results were presented as a poster at the 2016 Population Approach Group Europe (PAGE) meeting.

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Authors and Affiliations

  1. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr 31, 12169, Berlin, Germany

    Johanna Melin, Zinnia P. Parra-Guillen, Niklas Hartung & Charlotte Kloft

  2. Graduate Research Training Program, PharMetrX, Berlin, Germany

    Johanna Melin

  3. Institute of Mathematics, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476, Potsdam, Germany

    Niklas Hartung & Wilhelm Huisinga

  4. Department of Oncology and Metabolism, University of Sheffield, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK

    Richard J. Ross

  5. Diurnal Limited, Cardiff Medicentre, Heath Park, Cardiff, CF14 4UJ, UK

    Martin J. Whitaker

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  1. Johanna Melin
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Correspondence to Charlotte Kloft.

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Funding

The work was carried out under a Cooperation Agreement between Freie Universitaet and Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN).

Conflict of interest

Johanna Melin, Zinnia P. Parra Guillen and Niklas Hartung have no conflicts of interest. Richard Ross is a director of Diurnal Ltd and has stock options. Martin Whitaker is an employee and director of Diurnal Ltd and has stock options. Charlotte Kloft reports a research grant to Freie Universitaet Berlin from Diurnal funded by the European Commission FP7 Grant (No. 281654 TAIN) and grants from the Innovative Medicines Initiative-Joint Undertaking (‘DDMoRe’). Charlotte Kloft and Wilhelm Huisinga report grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd, Merck KGaA and SANOFI).

Ethical approval

Data from two studies (Registered EudraCT numbers: 2013-000260-28 and 2013-000259-42) were used for this analysis. Both studies were approved by the South East Wales Research Ethics committee and performed according to the 1964 Helsinki Declaration and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Melin, J., Parra-Guillen, Z.P., Hartung, N. et al. Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults. Clin Pharmacokinet 57, 515–527 (2018). https://doi.org/10.1007/s40262-017-0575-8

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  • DOI: https://doi.org/10.1007/s40262-017-0575-8

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