Pharmacokinetic/pharmacodynamic evaluation of deflazacort in comparison to methylprednisolone and prednisolone.
OBJECTIVE
The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone.


METHODS
Methylprednisolone, prednisolone and the active metabolite of 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 pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes.


RESULTS
Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort 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 half-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 effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds.


CONCLUSIONS
Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.
D000042:Absorption; D000284:Administration, Oral; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018592:Cross-Over Studies; D005069:Evaluation Studies as Topic; D005260:Female; D005938:Glucocorticoids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008775:Methylprednisolone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011239:Prednisolone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011282:Pregnenediones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D011355:Prodrugs; D011239:Prednisolone; C021988:deflazacort; D008775:Methylprednisolone