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

A physiologic pharmacodynamic model was developed to jointly characterize t he effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients Me thylprednisolone (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, an d 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 inhibiti on function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cell s in blood after single and multiple doses of MP. The potency of MP for sup pression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorh ythmic nature of the basal T-helper cells in blood was well described as un der the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells wa s IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can als o 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 t reatment were adequately described by these extended indirect response mode ls.