Modeling interactions between adrenal suppression and T-helper lymphocyte trafficking during multiple dosing of methylprednisolone.
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.
Chow
F S
FS
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, New York 14260, USA.
Sharma
A
A
Jusko
W J
WJ
D000311:Adrenal Glands / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002940:Circadian Rhythm; D004334:Drug Administration Schedule; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007165:Immunosuppression Therapy; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*
D006854:Hydrocortisone; D008775:Methylprednisolone