Advertisement

Clinical Pharmacokinetics

, Volume 57, Issue 4, pp 515–527 | Cite as

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

  • Johanna Melin
  • Zinnia P. Parra-Guillen
  • Niklas Hartung
  • Wilhelm Huisinga
  • Richard J. Ross
  • Martin J. Whitaker
  • Charlotte KloftEmail author
Original Research Article

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.

Notes

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.

Compliance with Ethical Standards

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.

Supplementary material

40262_2017_575_MOESM1_ESM.docx (173 kb)
Supplementary material 1 (DOCX 174 kb)
40262_2017_575_MOESM2_ESM.docx (55 kb)
Supplementary material 2 (DOCX 55 kb)
40262_2017_575_MOESM3_ESM.docx (202 kb)
Supplementary material 3 (DOCX 202 kb)

References

  1. 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.CrossRefPubMedGoogle Scholar
  2. 2.
    Porter J, Blair J, Ross RJ. Is physiological glucocorticoid replacement important in children? Arch Dis Child. 2017;102:199–205.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 10.
    Lentjes EGWM. Romijn FHTPM. Temperature-dependent cortisol distribution among the blood compartments in man. J Clin Endocrinol Metab. 1999;84:682–7.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 16.
    World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–4.CrossRefGoogle Scholar
  17. 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. 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. 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.CrossRefPubMedGoogle Scholar
  20. 20.
    Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides (1989–2009). Ellicott City: Icon Development Solutions; 2009.Google Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 22.
    Dansirikul C, Silber HE, Karlsson MO. Approaches to handling pharmacodynamic baseline responses. J Pharmacokinet Pharmacodyn. 2008;35:269–83.CrossRefPubMedGoogle Scholar
  23. 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. 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. 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.PubMedGoogle Scholar
  26. 26.
    Rohatgi A. WebPlotDigitizer. http://arohatgi.info/WebPlotDigitizer. Accessed 5 Oct 2016.
  27. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 31.
    Westphal U. Steroid-protein interactions. In: Gross F, Labhart A, Mann T, Samuels L (eds.) 1st edn. New York: Springer; 1971.Google Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 36.
    Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115–21.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 39.
    World Health Organisation. WHO child growth standards. 2006. http://www.who.int/childgrowth/standards/Technical_report.pdf. Accessed 19 Apr 2017.

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Johanna Melin
    • 1
    • 2
  • Zinnia P. Parra-Guillen
    • 1
  • Niklas Hartung
    • 1
    • 3
  • Wilhelm Huisinga
    • 3
  • Richard J. Ross
    • 4
  • Martin J. Whitaker
    • 5
  • Charlotte Kloft
    • 1
    Email author
  1. 1.Department of Clinical Pharmacy and Biochemistry, Institute of PharmacyFreie Universitaet BerlinBerlinGermany
  2. 2.Graduate Research Training ProgramPharMetrXBerlinGermany
  3. 3.Institute of MathematicsUniversity of PotsdamPotsdamGermany
  4. 4.Department of Oncology and MetabolismUniversity of Sheffield, Medical SchoolSheffieldUK
  5. 5.Diurnal LimitedCardiff MedicentreCardiffUK

Personalised recommendations