EVALUATION OF DOSE-RELATED PHARMACOKINETICS AND PHARMACODYNAMICS OF PREDNISOLONE IN MAN

The pharmacokinetic and pharmacodynamics of prednisolone were evaluate d in normal male volunteers. Seven subjects completed 3 phases: 16.4- and 49.2-mg iv prednisolone, and a phase with no drugs to assess basel ine responses. Plasma concentrations of prednisolone and urine concent rations of prednisolone and 5 metabolites were assayed by HPLC. Protei n binding of prednisolone was measured by ultrafiltration. The polyexp onential disposition of free and total plasma prednisolone were evalua ted and apparent parameters were compared between doses. Suppression o f plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic mode ls were used to relate total or free plasma prednisolone concentration s to each of these effects generating response parameters and IC50 (50 % inhibitory) concentrations common to both doses. The pharmacokinetic s of total drug were comparable to previous findings with CL and V(ss) increasing with dose. Free prednisolone exhibited slight capacity-lim ited elimination and distribution as CL and V(ss) decreased with the l arger dose. Pharmacodynamic models jointly fitting all three phases ch aracterized the suppression/trafficking phenomena equally well with us e of total or free drug concentrations. In each case the models provid ed realistic values of parameters relating to steroid sensitivity-in p articular IC50-and to the underlying physiology of the affected system s. This study comprehensively elucidates the complexities of prednisol one pharmacokinetics and demonstrates how plasma concentration-time pr ofiles of total of free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.