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Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone

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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.

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Author notes

  1. Fung-Sing Chow & Amarnath Sharma

    Present address: Drug Metabolism and Pharmacokinetics, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, 19406

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, New York, 14260

    Fung-Sing Chow, Amarnath Sharma & William J. Jusko

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Chow, FS., Sharma, A. & Jusko, W.J. Modeling Interactions between Adrenal Suppression and T-Helper Lymphocyte Trafficking during Multiple Dosing of Methylprednisolone. J Pharmacokinet Pharmacodyn 27, 559–575 (1999). https://doi.org/10.1023/A:1020974408657

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