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Modélisation pharmacocinétique - pharmacodynamique de la fludrocotisone par approche de population

Abstract : Introduction. Low doses of corticosteroids showed beneficial effects in septic shock patients. These favorable effects may be partly result from the stimulation of the mineralocorticoid receptors. This finding has led us to explore the pharmacokinetic and the effects on hemodynamic and biologic parameters of fludrocortisone which is a potent mineralocorticoid. Methods. In this work, a population approach modeling (nonlinear mixed effects modeling) was used to characterize the pharmacokinetic and the pharmacokinetic-pharmacodynamic relationship of fludrocortisone in healthy volunteers and the pharmacokinetic in septic shock patients. Results. In healthy volunteers after single oral administration alone or in combination with hydrocortisone, fludrocortisone 50 µg showed a short and similar plasma elimination half-life that intravenous hydrocortisone. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. Simulations suggested that the administration regimen of fludrocortisone should be reconsidered. In septic shock patient, a single oral dose of fludrocortisone at 50 µg yielded detectable plasma drug concentrations in two-thirds of adults with septic shock. Fludrocortisone pharmacokinetics showed a short plasma elimination half-life and a large inter-individual variability. These results suggested that an intravenous formulation of fludrocortisone would be useful to reduce its pharmacokinetic variability in septic patients. In healthy volunteers again, after 5 days of repeated oral administration, fludrocortisone improved pressor response to phenylephrine. This effect was observed only at the dose of 400 µg/day, suggesting that fludrocortisone at higher doses than previously administered (50 µg/day) may be useful to be effective. Furthermore, we showed that fludrocortisone had a short plasma half-live (1.94 h) which is consistent with our previously published study. After 5 day of repeated administration, fludrocortisone significantly increased blood pressure. This effect was more marked at the dose of 400 µg/day. Conclusion. Our results argue in favor of potential beneficial effects that fludrocortisone could have in septic shock patients. An evaluation of the effectiveness of fludrocortisone in these patients is now possible and necessary to confirm our results.
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Noureddine Hamitouche. Modélisation pharmacocinétique - pharmacodynamique de la fludrocotisone par approche de population. Médecine humaine et pathologie. Université Rennes 1, 2017. Français. ⟨NNT : 2017REN1B026⟩. ⟨tel-01830055⟩



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