Population pharmacokinetic approach to compare oral and i.v. administration of etoposide.
The antitumor effect of etoposide (ETO) may be related to duration of exposure 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 AUC, pAUC) were used to compare pharmacokinetic profiles after oral and short time i.v. (1 h infusion) administration of identical ETO doses (100 mg/m2). Patients included in this study received i.v. (18 patients, short-term infusions) or oral (16 patients) ETO on 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 ETO was associated with the same time of exposure to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. administration. By contrast, time of exposure to the probably more myelotoxic concentration range above 3 mg/l was significantly shorter and the related pAUC was highly significantly lower after oral than after i.v. administration. These findings demonstrate that oral ETO therapy is at least equivalent to short time i.v. therapy in terms of achieving specific target concentration ranges and avoiding peak concentrations.
Würthwein
G
G
Department of Pediatric Hematology and Oncology, University of Münster, Germany.
Krümpelmann
S
S
Tillmann
B
B
Real
E
E
Schulze-Westhoff
P
P
Jürgens
H
H
Boos
J
J
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide