Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.
OBJECTIVE
We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan.


METHODS
Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system.


RESULTS
All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI).


CONCLUSIONS
The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.
Mross
K
K
Department of Internal Medicine, University Hospital Eppendorf, Hamburg, Germany.
Bewermeier
P
P
Krüger
W
W
Stockschläder
M
M
Zander
A
A
Hossfeld
D K
DK
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics; D002066:Busulfan / Q000008:administration & dosage / Q000494:pharmacology; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005047:Etoposide / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D005260:Female; D006402:Hematologic Diseases / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism; D010672:Phenytoin / Q000494:pharmacology; D013810:Therapeutic Equivalency
D010672:Phenytoin; D005047:Etoposide; D002066:Busulfan