Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cytostatics, plant alkaloids and other natural products, podophyllotoxin derivatives.
ATC code: L01CB01.

Mechanism of action
The main effect of etoposide appears to be at the late S and early G2 portion of the cell cycle in mammalian cells. Two dose-dependent responses are seen: At high concentrations (10 mcg/mL or more), cells entering mitosis are lysed; at low concentrations (0.3 to 10 mcg/mL), cells are inhibited from entering prophase. Microtubule assembly is not affected.
The predominant macromolecular effect of etoposide seems to be the rupture of the double strand by an interaction with DNA- topoisomerase II or by the formation of free radicals. Etoposide has been shown to cause metaphase arrest in chick fibroblasts.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
After either intravenous infusion or oral capsule administration, the C max and AUC values exhibit marked intra- and inter-subject variability.

Distribution
The mean volumes of distribution at steady state range from 18 to 29 liters. Etoposide shows low penetration into the CSF. In vitro, etoposide is highly protein-bound (97 %) to human plasma proteins.
Etoposide binding ratio correlates directly with serum albumin in cancer patients and normal volunteers (see section 4.4). Unbound fraction of etoposide correlates significantly with bilirubin in cancer patients.

Biotransformation
The hydroxyacid metabolite [4' dimethyl-epipodophyllic acid-9-(4,6 0-ethylidene-β-D- glucopyranoside)], formed by opening of the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer. Glucuronide and/or sulfate conjugates of etoposide are also excreted in human urine. In addition, O- 
demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

Elimination
On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours.Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100 to 600 mg/m2. After intravenous administration of 14C-etoposide (100 to 124 mg/m2), mean recovery of radioactivity in the urine was 56% (45% of the dose was excreted as etoposide) and faecal recovery of radioactivity was 44% of the administered dose at 120 hours.

Linearity/Non-linearity
Total body clearance and the terminal elimination half-life are independent of dose over a range 100 to 600 mg/m2. Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose.

Renal impairment
Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and higher steady state volume of distribution (see section 4.2).

Hepatic impairment
In adult cancer patients with liver dysfunction, total body clearance of etoposide is not reduced.

Elderly population
Although minor differences in pharmacokinetic parameters between patients ≤65 years and >65 years of age have been observed, these are not considered clinically significant.

Paediatric population
In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m 2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion.
The effect of renal disease on plasma etoposide clearance is not known in children. In children, elevated SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.
An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children.

Gender
Although minor differences in pharmacokinetic parameters between genders have been observed, these are not considered clinically significant.

Drug interactions
In a study of the effects of other therapeutic agents on in vitro binding of 14C-etoposide to human serum proteins, only phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations generally achieved in vivo (see section 4.5).