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


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.


fludrocortisone hydrocortisone modeling pharmacodynamics pharmacokinetics 



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)


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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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