PHARMACOKINETIC-PHARMACODYNAMIC EVALUATION OF DEFLAZACORT IN COMPARISON TO METHYLPREDNISOLONE AND PREDNISOLONE

The pharmacokinetics and pharmacodynamics of deflazacort after oral ad ministration (30 mg) to healthy volunteers were determined and compare d with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite o f deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokineti c-pharmacodynamic (PK-PD) model was applied to link corticosteroid con centrations to the effect on lymphocytes and granulocytes. Results. De flazacort is an inactive prodrug which is converted rapidly to the act ive metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-d esacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml . h, and the terminal h alf-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed eff ects. The results were consistent with reported values for glucocortic oid receptor binding affinities for the investigated compounds. Conclu sions. Due to the short pharmacokinetic half-life of its active metabo lite, pharmacodynamic effects of deflazacort are of shorter duration t han those of methylprednisolone and prednisolone. The PK-PD model allo ws good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.