A Pharmacokinetic/pharmacodynamic Approach to Predict Total Prednisolone Concentrations in Human Plasma

Overview

Journal J Pharmacokinet Pharmacodyn

Publisher Springer

Specialty Pharmacology

Date 2007 Feb 24

PMID 17318442

Citations 13

Authors

J Xu

J Winkler

H Derendorf

Affiliations

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Abstract

Prednisolone and prednisone are two widely used corticosteroids for various inflammatory and immune diseases. Prednisolone is the active form of prednisone in vivo. Total prednisolone in plasma exhibits nonlinear pharmacokinetics mainly due to its nonlinear protein binding. Other factors such as reversible metabolism (or interconversion between prednisolone and prednisone), competitive protein binding from endogenous cortisol, cortisol circadian rhythm, and prednisolone mediated cortisol suppression complicate prednisolone pharmacokinetics. This study was aimed to develop a new approach to describe the nonlinear pharmacokinetics of total prednisolone and predict total prednisolone concentrations in plasma. Based on literature datasets, a linear two-compartment pharmacokinetic model was developed to adequately describe the reversible metabolism between free prednisone and prednisolone. Cortisol and prednisolone protein binding were described via the sum of a Langmuir and linear type binding. The endogenous cortisol circadian rhythm and cortisol suppression during prednisone or prednisolone exposure were described with a previously reported linear release rate pharmacokinetic/pharmacodynamic (PK/PD) model. By combining the pharmacokinetic models for free prednisone and prednisolone, the linear release rate model for cortisol suppression, and competitive protein binding between cortisol and prednisolone, we were able to predict total prednisolone concentrations in plasma. The predicted total prednisolone concentrations in plasma were in good agreement with the literature reported data. Thus, this PK/PD approach shows that the combination of nonlinear protein binding, cortisol circadian rhythm, and cortisol suppression could account for the nonlinearity of total prednisolone. In addition, it also allows a valid prediction of total prednisolone in plasma after either prednisone or prednisolone administration.

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References

Gambertoglio J, Amend Jr W, Benet L . Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: a review. J Pharmacokinet Biopharm. 1980; 8(1):1-52. DOI: 10.1007/BF01059447. View

FERRY J, Wagner J . The nonlinear pharmacokinetics of prednisone and prednisolone. II. Plasma protein binding of prednisone and prednisolone in rabbit and human plasma. Biopharm Drug Dispos. 1987; 8(3):261-72. DOI: 10.1002/bdd.2510080307. View

Rose J, Yurchak A, Jusko W . Dose dependent pharmacokinetics of prednisone and prednisolone in man. J Pharmacokinet Biopharm. 1981; 9(4):389-417. DOI: 10.1007/BF01060885. View

Frey B, Frey F . Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet. 1990; 19(2):126-46. DOI: 10.2165/00003088-199019020-00003. View

Chakraborty A, Blum R, Mis S, Cutler D, Jusko W . Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers. J Clin Pharmacol. 1999; 39(6):624-35. DOI: 10.1177/00912709922008137. View

Frey F, Frey B, GREITHER A, Benet L . Prednisolone clearance at steady state in dogs. J Pharmacol Exp Ther. 1980; 215(2):287-91. View

Chakraborty A, Krzyzanski W, Jusko W . Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods. J Pharmacokinet Biopharm. 1999; 27(1):23-43. DOI: 10.1023/a:1020678628317. View

Jusko W, Rose J . Monitoring prednisone and prednisolone. Ther Drug Monit. 1980; 2(2):169-76. DOI: 10.1097/00007691-198004000-00011. View

Rocci Jr M, DAmbrosio R, Johnson N, Jusko W . Prednisolone binding to albumin and transcortin in the presence of cortisol. Biochem Pharmacol. 1982; 31(3):289-92. DOI: 10.1016/0006-2952(82)90172-1. View

10.

Koopmans R, Braat M, Oosterhuis B, van Boxtel C . Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model. J Pharmacol Exp Ther. 1992; 262(2):503-8. View

11.

Pickup M, Lowe J, Leatham P, Rhind V, WRIGHT V, Downie W . Dose dependent pharmacokinetics of prednisolone. Eur J Clin Pharmacol. 1977; 12(3):213-9. DOI: 10.1007/BF00609864. View

12.

Baxter J, Rousseau G . Glucocorticoid hormone action: an overview. Monogr Endocrinol. 1979; 12:1-24. DOI: 10.1007/978-3-642-81265-1_1. View

13.

Huang M, Jusko W . Nonlinear pharmacokinetics and interconversion of prednisolone and prednisone in rats. J Pharmacokinet Biopharm. 1990; 18(5):401-21. DOI: 10.1007/BF01061702. View

14.

Boudinot F, Jusko W . Plasma protein binding interaction of prednisone and prednisolone. J Steroid Biochem. 1984; 21(3):337-9. DOI: 10.1016/0022-4731(84)90288-7. View

15.

FERRY J, Horvath A, BEKERSKY I, Heath E, Ryan C, Colburn W . Relative and absolute bioavailability of prednisone and prednisolone after separate oral and intravenous doses. J Clin Pharmacol. 1988; 28(1):81-7. DOI: 10.1002/j.1552-4604.1988.tb03105.x. View

16.

Garg V, Jusko W . Bioavailability and reversible metabolism of prednisone and prednisolone in man. Biopharm Drug Dispos. 1994; 15(2):163-72. DOI: 10.1002/bdd.2510150208. View

17.

Frey F, Ruegsegger M, Frey B . The dose-dependent systemic availability of prednisone: one reason for the reduced biological effect of alternate-day prednisone. Br J Clin Pharmacol. 1986; 21(2):183-9. PMC: 1400906. DOI: 10.1111/j.1365-2125.1986.tb05173.x. View

18.

Gustavson L, Benet L . The macromolecular binding of prednisone in plasma of healthy volunteers including pregnant women and oral contraceptive users. J Pharmacokinet Biopharm. 1985; 13(6):561-9. DOI: 10.1007/BF01058901. View

19.

Schwartz J, Mukhopadhyay S, Porras A, Viswanathan-Aiyer K, Adcock S, Ebel D . Effect of rofecoxib on prednisolone and prednisone pharmacokinetics in healthy subjects. J Clin Pharmacol. 2003; 43(2):187-92. DOI: 10.1177/0091270002239828. View

20.

Blum R, Schwartz K, Jusko W . Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J Clin Pharmacol. 2001; 41(11):1195-205. DOI: 10.1177/00912700122012742. View