Modeling interactions between adrenal suppression and T-helper lymphocyte trafficking during multiple dosing of methylprednisolone

J Pharmacokinet Biopharm. 1999 Dec;27(6):559-75. doi: 10.1023/a:1020974408657.

Abstract

A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenal Glands / drug effects*
  • Adrenal Glands / immunology
  • Adrenal Glands / metabolism
  • Circadian Rhythm
  • Drug Administration Schedule
  • Humans
  • Hydrocortisone / blood
  • Hydrocortisone / metabolism
  • Immunosuppression Therapy*
  • Male
  • Methylprednisolone / administration & dosage*
  • Methylprednisolone / pharmacokinetics
  • Methylprednisolone / pharmacology
  • Models, Biological*
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Hydrocortisone
  • Methylprednisolone