PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENT OF BIOAVAILABILITY FOR2 PRODRUGS OF METHYLPREDNISOLONE

Aims The aim of this study was to establish whether pharmacokinetic di fferences between two pro-drugs of methylprednisolone (MP) are Likely to be of clinical significance. Methods This study was a single-blind, randomized, crossover design comparing the bioequivalence of MP relea sed from th pro-drugs Promedrol (MP suleptanate) and Solu-Medrol (MP s uccinate) after a single 250 mg (MP equivalent) intramuscular injectio n to 20 healthy male volunteers. Bioequivalence was assessed by conven tional pharmacokinetic analysis, by measuring pharmacodynamic response s plus a novel approach using pharmacokinetic/pharmacodynamic modeling . The main measure of pharmacodynamic response was whole blood histami ne (WBH), a measure of basophil numbers. Results The MP C-max was less for MP suleptanate due to a longer absorption half-life of the prodru g from the intramuscular injection site. The bioavailability of MP was equivalent when based on AUC with a MP suleptanate median 108% of the MP succinate value (90% CI: 102-114%). For C-max the MP suleptanate m edian was 81% of the MP succinate value (90% CI: 75-88%). The t(max) f or MP from MP suleptanate was delayed relative to MP succinate. The me dian difference was 200% (90% non-parametric CI: 141-283%). The area u nder the WBH effect-time curve (AUEC) and the maximum response (E-max) were found to be equivalent (90% CI: 98-113% and 93-109% respectively ). The maximum changes in other white blood cell counts, blood glucose concentration and the parameters of the pharmacodynamic sigmoid E max model (EC50, E-max and gamma) were also not significantly different b etween prodrugs. Conclusions MP suleptane is an acceptable pharmaceuti cal alternative to MP succinate. The used of both pharmacokinetic and pharmacodynamic response data together gives greater confidence in the conclusions compared with those based only on conventional pharmacoki netic bioequivalence analysis.