Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.

PURPOSE: 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. PATIENTS AND 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). CONCLUSION: 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.

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)

Inhibition of CFU-C growth by VP-16 containing plasma samples obtained from patients after conditioning therapy for bone marrow transplantation.

The introduction of VP-16 into high-dose therapy regimens used for conditioning before BMT or PBSCT has resulted in higher remission rates and prolonged disease-free survival, even in high risk patients. VP-16 levels have been measured in plasma at the time of transplantation. The question is, is there a biological activity that corresponds with the risk of delayed engraftment or graft failure? We investigated the inhibitory effects of plasma samples obtained from patients under high-dose VP-16 therapy on the growth of human bone marrow progenitor cells. Bone marrow cells from healthy donors were exposed to the plasma samples and seeded into methylcellulose-culture (CFU-C-assay). We found a dose dependent CFU-C inhibition related to VP-16 plasma levels at the time of transplantation (k = 0.769, P < 0.01). There were signs of a correlation between CFU-C growth inhibition at the time of BMT and haematological recovery (k = 0.656, P < 0.05) between CFU-C inhibition and the time until leucocytes reached 0.2 x 10(9)/l. Patients with CFU-C growth inhibition at the time of BMT may show delayed engraftment of leucocytes and that there might be a correlation with VP-16 levels, but further investigation is necessary to determine the significance of the latter thesis and if VP-16 plasma levels could lead to failure of engraftment. We recommend a minimum time interval between VP-16 infusion and graft transplantation of 72 h.

The pharmacokinetics and toxicity of two application schedules with high-dose VP-16 in patients receiving an allogeneic bone marrow transplantation.

BACKGROUND: Etoposide is one of the few drugs being used in conditioning regimens because of the ease with which its dosage can be escalated by a factor of 6 compared to the normal dose. The best schedule in high-dose chemotherapy is not known. PATIENTS AND METHODS: We evaluated the pharmacokinetics (PK) of high-dose VP-16 during two different schedules (6-hour and 3 x 1-hour infusions) and the toxicity of the two application modes in patients with leukemia who underwent allogeneic bone marrow transplantation. RESULTS: A significant difference (p = 0.008) in the volume of distribution at steady state was observed. The mean Vss was 0.21 L/kg in the 6-hour group and 0.36 in the 3 x 1-hour group. The total drug exposure time with plasma levels > 100 ng/ml is significantly longer in the 'split' group (74 vs. 143 h). Other PK parameters such as plasma clearance and area under the curve were not significantly different. Leukocyte recovery to WBC levels > 0.2 and > 0.5/nl as well as platelet recovery to stable counts > 50/nl was significantly (p = 0.002, 0.009 and 0.04) prolonged in the 'split' group (3.7 vs. 12.3, 8.3 vs. 14.3 and 25 vs. 35 d). The liver toxicity as indicated by bilirubin peak levels was significantly (p = 0.02) more severe in the 'split' group (1.7 vs. 5.4 mg/dl). CONCLUSION: The area under the curve as a measure of total drug exposure cannot be correlated to the observed higher toxicity in the patient group with the 'split' application mode. The drug exposure time as well as the three high peak plasma levels may be more important.