Population pharmacokinetic approach to compare oral and i.v. administration of etoposide

The antitumor effect of etoposide (ETO) may be related to duration of expos ure to a relatively low serum level while myelosuppression may be dependent on peak ETO serum levels, With regard to such therapeutic ranges, duration of exposure to predefined plasma ETO concentration ranges and the related AUC (expressed as percent of total AUG, pAUC) were used to compare pharmaco kinetic profiles after oral and short time i.v. (1 h infusion) administrati on of identical 870 doses (100 mg/m(2)), Patients included in this study re ceived i.v. (18 patients, short-term infusions) or oral (16 patients) ETO o n different treatment schedules. Plasma ETO concentrations were determined by HPLC and population pharmacokinetic parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability' of 59%, oral administration of 870 was associated with the same time of exposure to a predefined 'therapeu tic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. a dministration. By contrast, time of exposure to the probably more myelotoxi c concentration range above 3 mg/l was significantly shorter and the relate d pAUC was highly significantly lower after oral than after i.v, administra tion. These findings demonstrate that oral ETO therapy is at least equivale nt to short time i.v, therapy in terms of achieving specific target concent ration ranges and avoiding peak concentrations. [(C) 1999 Lippincott Willia ms & Wilkins.].