title: Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers.
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.
authors.affiliation: Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France.|Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France.
authors.forename: Noureddine
authors.initials: N
authors.lastname: Hamitouche
authors.affiliation: Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Comets
authors.affiliation: Department of Pharmacology and Toxicology, Raymond Poincaré University Hospital, Garches, France.
authors.forename: Mégane
authors.initials: M
authors.lastname: Ribot
authors.affiliation: Department of Pharmacology and Toxicology, Raymond Poincaré University Hospital, Garches, France.|Inserm U-1173, Versailles Saint-Quentin University, Versailles, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Alvarez
authors.affiliation: Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France.|Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France.|Department of Biological and Clinical Pharmacology and Pharmacovigilance, Rennes University Hospital, Rennes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bellissant
authors.affiliation: Inserm, CIC 1414 Clinical Investigation Centre, Rennes, France. bruno.laviolle@chu-rennes.fr.|Laboratory of Experimental and Clinical Pharmacology, Rennes 1 University, Rennes, France. bruno.laviolle@chu-rennes.fr.|Department of Biological and Clinical Pharmacology and Pharmacovigilance, Rennes University Hospital, Rennes, France. bruno.laviolle@chu-rennes.fr.
authors.forename: Bruno
authors.initials: B
authors.lastname: Laviolle
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005438:Fludrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008962:Models, Theoretical; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D005438:Fludrocortisone; D006854:Hydrocortisone
keywords: fludrocortisone; hydrocortisone; modeling; pharmacodynamics; pharmacokinetics