The Pharmacokinetics of Epipodopyllotoxins — Clinical Relevance

Abstract

Etoposide (VP-16) is a semisynthetic derivative of podophyllotoxin, an anticancer drug that has been used for more than 1000 years [1]. VP-16 is a phase-specific drug, acting in the late S or early G2 phases of the cell cycle [2]. The drug has been very active in germ cell tumors, small cell lung cancer, lymphomas and leucemias. For many cytotoxic drugs, an escalation of drug dosage usually leads to an increased antitumor effect. The limited toxicity, primarily myelosuppression, of VP-16 at the standard dose levels (300–500 mg/m²) makes it a suitable drug for much higher dosages. In fact the dosages administered for preparatory chemotherapy regimens in allogeneic and autologous bone marrow transplantation for hematologic malignancies are 6–10 times higher (60 mg/kg or 3000 mg/m²). Nevertheless, the optimal schedule for high-dose VP-16 chemotherapy has to be determined. In vitro studies have clearly demonstrated that the duration of cell exposure to etoposide dictates the drug’s degree of tumorcell kill [3]. To achieve the same degree of cell kill in e.g. small cell lung cancer lines, 100 times the 24 hour incubation dose of VP-16 was required in a 1 hour exposure [4]. The results within clinical trials were similar. In case of five daily infusions of VP-16 in patients with small cell lung cancer this application mode (5 day split) was greatly superior to a 24 hour infusion [5]. In high dose regimens containing VP-16 it is a common procedure to administer the total VP-16 drug amount within a short infusion time (6–10 hours) [6]. The most fundamental question relates to the optimal schedule of etoposide in the high dose setting. It is possible that the optimal etoposide schedule and dose varies from patient to patient and tumor to tumor depending on the intra-individual capacities for clearance and metabolization and on the variable proportion of cycling cells open to attack by such a phase-specific action of VP-16. Within the bone marrow transplantation (BMT) project of the University Hospital in Hamburg the pharmacokinetic of three different schedules for high-dose VP-16 was studied in patients, receiving etoposide, cyclophosphamide and busulfan as conditioning chemotherapy regimen before BMT. Three sequential pharmacokinetic studies have been performed using different schedules for VP-16 administration for patients with hematological malignancies. The first study consisted of a 6 hour infusion schedule, the second investigation used a 34 hour infusion schedule and the third tested a 3-day regimen with 1 hour infusions every 24 hours.