PHARMACOKINETICS AND PHARMACODYNAMICS OF CLOPREDNOL

The pharmacokinetics and pharmacodynamics of cloprednol after oral adm inistration in doses of 2.5 to 15 mg to healthy volunteers were determ ined. The half-life of cloprednol ranged from 1.8 h to 2.7 h, the oral clearance (CL/F) was determined to be 15 - 22 1/h. Since cloprednol s hows nonlinear plasma protein binding, the plasma concentrations were converted to their free, unbound concentrations for the PK/PD-analysis . Due to this nonlinearity, the half-life of free, unbound cloprednol was shorter than that of the total drug. For the assessment of pharmac odynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK/PD) approach using a modified E(max)-model was applied to link unbound corticostero id concentrations to the effect on lymphocytes and granulocytes. The E so value for unbound cloprednol ranged from 3.6 to 4.7 ng/ml and 1.2 t o 4.6 ng/ml for granulocytes and lymphocytes, respectively. The PK/PD model allowed a good prediction of the observed effects and was consis tent with reported values for glucocorticoid receptor binding affiniti es for cloprednol.