Teniposide

Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G₂ phase of the cell cycle, thus preventing cells from entering mitosis.

Teniposide causes dose-dependent single- and double-stranded breaks in DNA and DNAprotein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate.

Teniposide has a broad spectrum of in vivo antitumor activity against murine tumors, including hematologic malignancies and various solid tumors. Notably, teniposide is active against sublines of certain murine leukemias with acquired resistance to cisplatin, doxorubicin, amsacrine, daunorubicin, mitoxantrone, or vincristine.

Plasma drug levels declined biexponentially following intravenous infusion (155 mg/m² over 1 to 2.5 hours) of teniposide given to 8 children (4-11 years old) with newly diagnosed acute lymphoblastic leukemia (ALL). The observed average pharmacokinetic parameters and associated coefficients of variation (CV%) based on a two-compartmental model analysis of the data are as follows:

There appears to be some association between an increase in serum alkaline phosphatase or gamma glutamyl-transpeptidase and a decrease in plasma clearance of teniposide. Therefore, caution should be exercised if teniposide is to be administered to patients with hepatic dysfunction.

In adults, at doses of 100 to 333 mg/m²/day, plasma levels increased linearly with dose. Drug accumulation in adult patients did not occur after daily administration of teniposide for 3 days. In pediatric patients, maximum plasma concentrations (C_max) after infusions of 137 to 203 mg/m² over a period of 1 to 2 hours exceeded 40 mcg/mL; by 20 to 24 hours after infusion plasma levels were generally <2 mcg/mL.

Renal clearance of parent teniposide accounts for about 10% of total body clearance. In adults, after intravenous administration of 10 mg/kg or 67 mg/m² of tritium-labeled teniposide, 44% of the radiolabel was recovered in urine (parent drug and metabolites) within 120 hours after dosing. From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the dose.

Mean steady-state volumes of distribution range from 8 to 44 L/m² for adults and 3 to 11 L/m² for children. The blood-brain barrier appears to limit diffusion of teniposide into the brain, although in a study in patients with brain tumors, CSF levels of teniposide were higher than CSF levels reported in other studies of patients who did not have brain tumors.

Teniposide is highly protein bound. In vitro plasma protein binding of teniposide is >99%. The high affinity of teniposide for plasma proteins may be an important factor in limiting distribution of drug within the body. Steady-state volume of distribution of the drug increases with a decrease in plasma albumin levels. Therefore, careful monitoring of children with hypoalbuminemia is indicated during therapy. Levels of teniposide in saliva, CSF, and malignant ascites fluid are low relative to simultaneously measured plasma levels.

The pharmacokinetic characteristics of teniposide differ from those of etoposide, another podophyllotoxin. Teniposide is more extensively bound to plasma proteins and its cellular uptake is greater. Teniposide also has a lower systemic clearance, a longer elimination half-life, and is excreted in the urine as parent drug to a lesser extent than etoposide.