Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids

Bernd Meibohm, H. Derendorf, H. Möllmann, P. Fröhlich, A. Tromm, M. Wagner, S. Homrighausen, M. Krieg, G. Hochhaus

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objective: Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol. Methods: In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment. Results: The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum corrisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 ± 0.034, 0.22 ± 0.13 and 26.3 ± 15.0 ng/ml (placebo group 15.4 ± 3.4 ng/ml), respectively. Conclusions: The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.

Original languageEnglish (US)
Pages (from-to)367-376
Number of pages10
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume37
Issue number8
StatePublished - Aug 28 1999

Fingerprint

Lymphopenia
Budesonide
Hydrocortisone
Adrenal Cortex Hormones
Pharmacokinetics
Lymphocytes
Placebos
Circadian Rhythm
Lymphocyte Count
Serum
Protein Binding
Volunteers
Immune System
Biomarkers
Pharmacology

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids. / Meibohm, Bernd; Derendorf, H.; Möllmann, H.; Fröhlich, P.; Tromm, A.; Wagner, M.; Homrighausen, S.; Krieg, M.; Hochhaus, G.

In: International Journal of Clinical Pharmacology and Therapeutics, Vol. 37, No. 8, 28.08.1999, p. 367-376.

Research output: Contribution to journalArticle

Meibohm, B, Derendorf, H, Möllmann, H, Fröhlich, P, Tromm, A, Wagner, M, Homrighausen, S, Krieg, M & Hochhaus, G 1999, 'Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids', International Journal of Clinical Pharmacology and Therapeutics, vol. 37, no. 8, pp. 367-376.
Meibohm, Bernd ; Derendorf, H. ; Möllmann, H. ; Fröhlich, P. ; Tromm, A. ; Wagner, M. ; Homrighausen, S. ; Krieg, M. ; Hochhaus, G. / Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids. In: International Journal of Clinical Pharmacology and Therapeutics. 1999 ; Vol. 37, No. 8. pp. 367-376.
@article{c790e534e95c45b886c0d17f01e2df90,
title = "Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids",
abstract = "Objective: Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol. Methods: In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment. Results: The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum corrisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 ± 0.034, 0.22 ± 0.13 and 26.3 ± 15.0 ng/ml (placebo group 15.4 ± 3.4 ng/ml), respectively. Conclusions: The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.",
author = "Bernd Meibohm and H. Derendorf and H. M{\"o}llmann and P. Fr{\"o}hlich and A. Tromm and M. Wagner and S. Homrighausen and M. Krieg and G. Hochhaus",
year = "1999",
month = "8",
day = "28",
language = "English (US)",
volume = "37",
pages = "367--376",
journal = "International Journal of Clinical Pharmacology and Therapeutics",
issn = "0946-1965",
publisher = "Dustri-Verlag Dr. Karl Feistle",
number = "8",

}

TY - JOUR

T1 - Mechanism-based PK/PD model for the lymphocytopenia induced by endogenous and exogenous corticosteroids

AU - Meibohm, Bernd

AU - Derendorf, H.

AU - Möllmann, H.

AU - Fröhlich, P.

AU - Tromm, A.

AU - Wagner, M.

AU - Homrighausen, S.

AU - Krieg, M.

AU - Hochhaus, G.

PY - 1999/8/28

Y1 - 1999/8/28

N2 - Objective: Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol. Methods: In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment. Results: The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum corrisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 ± 0.034, 0.22 ± 0.13 and 26.3 ± 15.0 ng/ml (placebo group 15.4 ± 3.4 ng/ml), respectively. Conclusions: The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.

AB - Objective: Lymphocytopenia is a sensitive surrogate marker for the immunological effects of corticosteroids. This pharmacokinetic/pharmacodynamic (PK/PD) study investigated whether the circadian variation of blood lymphocytes observed after placebo is secondary to the circadian rhythm of endogenous cortisol, and developed based on this relationship an improved PK/PD model for a more sensitive description of the effect of low-dose corticosteroid therapy on blood lymphocytes considering the net activity of the exogenous corticosteroid budesonide and endogenous cortisol. Methods: In an open, parallel study design, 3 mg oral budesonide or placebo were given at 8.00 a.m., 4.00 p.m. and midnight to two groups of 12 volunteers. Lymphocyte counts and serum concentrations of budesonide and cortisol were monitored for 24 hours. A mechanism-based PK/PD model which considered the non-linear protein binding of cortisol and the budesonide-induced cortisol suppression was employed to relate changes in blood lymphocytes to free cortisol levels after placebo and to the net activity of free budesonide and free endogenous cortisol after active treatment. Results: The circadian rhythm of blood lymphocytes observed after placebo could inversely be related to the circadian rhythm of serum corrisol. After budesonide administration, lymphocyte counts could accurately be linked to the net activity of budesonide and endogenous cortisol. The resulting EC50 values for the effect of budesonide on cortisol, budesonide on lymphocytes and cortisol on lymphocytes were 0.063 ± 0.034, 0.22 ± 0.13 and 26.3 ± 15.0 ng/ml (placebo group 15.4 ± 3.4 ng/ml), respectively. Conclusions: The presented mechanism-based PK/PD model suggests that blood lymphocytes are under physiological control of cortisol. It further indicates that endogenous and exogenous corticosteroids and their pharmacological interaction need to be considered for modeling the effects of low doses of exogenous corticosteroids on the immune system.

UR - http://www.scopus.com/inward/record.url?scp=0032777479&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032777479&partnerID=8YFLogxK

M3 - Article

VL - 37

SP - 367

EP - 376

JO - International Journal of Clinical Pharmacology and Therapeutics

JF - International Journal of Clinical Pharmacology and Therapeutics

SN - 0946-1965

IS - 8

ER -