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

Abstract

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. 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. 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). 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.