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The AAPS Journal

, Volume 19, Issue 3, pp 727–735 | Cite as

Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers

  • Noureddine Hamitouche
  • Emmanuelle Comets
  • Mégane Ribot
  • Jean-Claude Alvarez
  • Eric Bellissant
  • Bruno LaviolleEmail author
Research Article

Abstract

This study aimed at describing the pharmacokinetics and the concentration-effect relationships of fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC50) was about 200 times lower for fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of fludrocortisone should be reconsidered.

KEY WORDS

fludrocortisone hydrocortisone modeling pharmacodynamics pharmacokinetics 

Notes

ACKNOWLEDGEMENTS

The authors thank Nolwenn Boissel, Viviane Fortuna, and Cecile Reminiac (research nurses, Clinical Investigation Unit, Inserm CIC 1414 Clinical Investigation Centre) for technical assistance and Stuart Byrom for English editing. We also thank Pr Djillali Annane for his comments on the results.

Supplementary material

12248_2016_41_MOESM1_ESM.docx (30 kb)
Table S1 (DOCX 29 kb)
12248_2016_41_Fig5_ESM.gif (23 kb)
Fig. S1

Goodness-of-fit plots for the final pharmacokinetic model of fludrocortisone. (a) Observations versus population predicted values; (b) Observations versus individual predicted values; (c) Normalized Prediction Distribution Errors (NPDE) versus time. Observations are plotted as closed circles and crosses show censored data (below the quantification limit) (GIF 22 kb)

12248_2016_41_MOESM2_ESM.eps (547 kb)
High resolution image (EPS 547 kb)
12248_2016_41_Fig6_ESM.gif (22 kb)
Fig. S2

Goodness-of-fit plots for the final pharmacokinetic model of hydrocortisone. (a) Observations versus population predicted values; (b) Observations versus individual predicted values; (c) Normalized Prediction Distribution Errors (NPDE) versus time. Observations are plotted as closed circles (GIF 21 kb)

12248_2016_41_MOESM3_ESM.eps (189 kb)
High resolution image (EPS 189 kb)
12248_2016_41_Fig7_ESM.gif (22 kb)
Fig. S3

Goodness-of-fit plots for the final pharmacokinetic-pharmacodynamic model. (a) Observations versus population predicted values; (b) Observations versus individual predicted values; (c) Normalized Prediction Distribution Errors (NPDE) versus time. Observations are plotted as closed circles (GIF 21 kb)

12248_2016_41_MOESM4_ESM.eps (381 kb)
High resolution image (EPS 380 kb)

References

  1. 1.
    Arlt W, Allolio B. Adrenal insufficiency. Lancet. 2003;361(9372):1881–93.CrossRefPubMedGoogle Scholar
  2. 2.
    Annane D, Sébille V, Charpentier C, Bollaert P-E, François B, Korach J-M, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862–71.CrossRefPubMedGoogle Scholar
  3. 3.
    Laviolle B, Annane D, Fougerou C, Bellissant E. Gluco- and mineralocorticoid biological effects of a 7-day treatment with low doses of hydrocortisone and fludrocortisone in septic shock. Intensive Care Med. 2012;38(8):1306–14.CrossRefPubMedGoogle Scholar
  4. 4.
    Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335(16):1206–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008;358(2):111–24.CrossRefPubMedGoogle Scholar
  6. 6.
    COIITSS Study Investigators, Annane D, Cariou A, Maxime V, Azoulay E, D’honneur G, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303(4):341–8.CrossRefGoogle Scholar
  7. 7.
    Annane D. Corticosteroids for severe sepsis: an evidence-based guide for physicians. Ann Intensive Care. 2011;1(1):7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Laviolle B, Le Maguet P, Verdier M-C, Massart C, Donal E, Lainé F, et al. Biological and hemodynamic effects of low doses of fludrocortisone and hydrocortisone, alone or in combination, in healthy volunteers with hypoaldosteronism. Clin Pharmacol Ther. 2010;88(2):183–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Vogt W, Fischer I, Ebenroth S, Appel S, Knedel M, Lücker PW, et al. [Pharmacokinetics of 9 -fluorhydrocortisone]. Arzneimittelforschung. 1971;21(8):1133–43.Google Scholar
  10. 10.
    Ribot M, Polito A, Grassin-Delyle S, Annane D, Alvarez J-C. Human plasma quantification of fludrocortisone using liquid chromatography coupled with atmospheric pressure chemical ionization mass spectrometry after low-dosage administration. Clin Chim Acta Int J Clin Chem. 2013;420:109–13.CrossRefGoogle Scholar
  11. 11.
    Chan PLS, Jacqmin P, Lavielle M, McFadyen L, Weatherley B. The use of the SAEM algorithm in MONOLIX software for estimation of population pharmacokinetic-pharmacodynamic-viral dynamics parameters of maraviroc in asymptomatic HIV subjects. J Pharmacokinet Pharmacodyn. 2011;38(1):41–61.CrossRefPubMedGoogle Scholar
  12. 12.
    Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.CrossRefPubMedGoogle Scholar
  13. 13.
    Bertrand J, Comets E, Mentre F. Comparison of model-based tests and selection strategies to detect genetic polymorphisms influencing pharmacokinetic parameters. J Biopharm Stat. 2008;18(6):1084–102.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Comets E, Brendel K, Mentré F. Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: the npde add-on package for R. Comput Methods Programs Biomed. 2008;90(2):154–66.CrossRefPubMedGoogle Scholar
  15. 15.
    Rohatagi S, Bye A, Mackie AE, Derendorf H. Mathematical modeling of cortisol circadian rhythm and cortisol suppression. Eur J Pharm Sci. 1996;4(6):341–50.CrossRefGoogle Scholar
  16. 16.
    Derendorf H, Hochhaus G, Meibohm B, Möllmann H, Barth J. Pharmacokinetics and pharmacodynamics of inhaled corticosteroids. J Allergy Clin Immunol. 1998;101(4 Pt 2):S440–446.CrossRefPubMedGoogle Scholar
  17. 17.
    Otte C, Jahn H, Yassouridis A, Arlt J, Stober N, Maass P, et al. The mineralocorticoid receptor agonist, fludrocortisone, inhibits pituitary-adrenal activity in humans after pre-treatment with metyrapone. Life Sci. 2003;73(14):1835–45.CrossRefPubMedGoogle Scholar
  18. 18.
    Gaddum JH. Theories of drug antagonism. Pharmacol Rev. 1957;9(2):211–8.PubMedGoogle Scholar
  19. 19.
    Greco WR, Bravo G, Parsons JC. The search for synergy: a critical review from a response surface perspective. Pharmacol Rev. 1995;47(2):331–85.PubMedGoogle Scholar
  20. 20.
    Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm. 1993;21(4):457–78.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Polito A, Hamitouche N, Ribot M, Polito A, Laviolle B, Bellissant E, et al. Pharmacokinetics of oral fludrocortisone in septic shock. Br J Clin Pharmacol 2016.Google Scholar
  22. 22.
    Toothaker RD, Craig WA, Welling PG. Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sci. 1982;71(10):1182–5.CrossRefPubMedGoogle Scholar
  23. 23.
    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(7):455–63.CrossRefPubMedGoogle Scholar
  24. 24.
    Derendorf H, Möllmann H, Barth J, Möllmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J Clin Pharmacol. 1991;31(5):473–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Thomson AH, Devers MC, Wallace AM, Grant D, Campbell K, Freel M, et al. Variability in hydrocortisone plasma and saliva pharmacokinetics following intravenous and oral administration to patients with adrenal insufficiency. Clin Endocrinol (Oxf). 2007;66(6):789–96.CrossRefGoogle Scholar
  26. 26.
    Banda J, Lakshmanan R, Vvs SP, Gudla SP, Prudhivi R. A highly sensitive method for the quantification of fludrocortisone in human plasma using ultra-high-performance liquid chromatography tandem mass spectrometry and its pharmacokinetic application. Biomed Chromatogr BMC 2015Google Scholar
  27. 27.
    Mitsky VP, Workman RJ, Nicholson WE, Vernikos J, Robertson RM, Robertson D. A sensitive radioimmunoassay for fludrocortisone in human plasma. Steroids. 1994;59(9):555–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Sheiner L, Wakefield J. Population modelling in drug development. Stat Methods Med Res. 1999;8(3):183–93.CrossRefPubMedGoogle Scholar
  29. 29.
    Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm. 1993;21(6):735–50.CrossRefPubMedGoogle Scholar
  30. 30.
    Hong Y, Mager DE, Blum RA, Jusko WJ. Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Pharm Res. 2007;24(6):1088–97.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Noureddine Hamitouche
    • 1
    • 2
  • Emmanuelle Comets
    • 1
  • Mégane Ribot
    • 3
  • Jean-Claude Alvarez
    • 3
    • 4
  • Eric Bellissant
    • 1
    • 2
    • 5
  • Bruno Laviolle
    • 1
    • 2
    • 5
    Email author
  1. 1.Inserm, CIC 1414 Clinical Investigation CentreRennesFrance
  2. 2.Laboratory of Experimental and Clinical PharmacologyRennes 1 UniversityRennesFrance
  3. 3.Department of Pharmacology and ToxicologyRaymond Poincaré University HospitalGarchesFrance
  4. 4.Inserm U-1173, Versailles Saint-Quentin UniversityVersaillesFrance
  5. 5.Department of Biological and Clinical Pharmacology and PharmacovigilanceRennes University HospitalRennesFrance

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