Pharmacokinetics of high-dose VP-16: 6-hour infusion versus 34-hour infusion.
VP-16 was administered in high doses (30-45 mg/kg) in combination with busulfan (BU) and cyclophosphamide (CY). The anticancer activity of VP-16 is thought to be schedule-dependent. We investigated a 6-h and a 34-h infusion of VP-16 to compare pharmacokinetic parameters and toxicity. Blood samples were taken from a total of 16 patients during infusion time (6 h and 34 h, respectively) and thereafter up to 2 days after bone marrow transplantation (BMT). VP-16 concentrations were measured in all plasma samples with HPLC technique and electrochemical detection and the results were analyzed with a pharmacokinetic data analysis system. All calculated pharmacokinetic parameters in the two patient groups were essentially similar. There were no statistically significant differences in half-lives, mean residence time, volume of distribution, total clearance and area under the curve. The treatment-related toxicity was not different between groups. The major difference was the maximal concentration in the case of 6-h infusions (122 +/- 35 micrograms/ml) and in the case of 34-h infusions (23.2 +/- 4.9 micrograms/ml) and the duration of VP-16 concentrations with > 10 and > 1 microgram/ml. Drug levels above these thresholds were always longer in case of 34-h infusions. In 8 of 16 patients VP-16 concentrations were measured in plasma samples at the time of BMT ranging from 80 to 820 ng/ml. The two different schedules for VP-16 administration, either given as a 6-h infusion or as a 34-h infusion, are bioequivalent in pharmacokinetic terms.(ABSTRACT TRUNCATED AT 250 WORDS)
University Hospital Eppendorf, Department of Internal Medicine, Hamburg, Germany.
K
K
Mross
P
P
Bewermeier
J
J
Reifke
W
W
Krüger
M
M
Stockschläder
A
A
Zander
D K
DK
Hossfeld
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006689:Hodgkin Disease / Q000628:therapy; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000628:therapy; D008297:Male; D013280:Stomatitis / Q000139:chemically induced
D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan