April 29, 2017
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Etopophos

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Etopophos




CLINICAL PHARMACOLOGY

Mechanism Of Action

Etoposide phosphate is a prodrug that is converted to its active moiety, etoposide, by dephosphorylation. Etoposide causes the induction of DNA strand breaks by an interaction with DNAtopoisomerase II or the formation of free radicals, leading to cell cycle arrest, primarily at the G2 stage of the cell cycle, and cell death.

Pharmacodynamics

Following intravenous administration of 90, 100, and 110 mg/m2 dose of ETOPOPHOS over 60 minutes, mean nadir values (expressed as percent decrease from baseline) for granulocytes, hemoglobin, and thrombocytes were 81.0 ± 16.5%, 21.4 ± 9.9%, and 44.1 ± 20.7%, respectively.

Pharmacokinetics

Following intravenous administration of an etoposide formulation, the area under the concentration time curve (AUC) and maximum plasma concentration (Cmax) values increased linearly and etoposide did not accumulate in the plasma following daily administration for 4 to 5 days.

Distribution

Following administration of an injectable etoposide formulation, the mean volume of distribution of etoposide at steady state was 18 to 29 liters.

Etoposide enters the CSF poorly.

In vitro, etoposide is 97% bound to human plasma proteins, primarily albumin.

Elimination

The terminal elimination half-life of etoposide ranges from 4 to 11 hours. Total body clearance values range from 33 to 48 mL/min.

Metabolism

Following intravenous administration of ETOPOPHOS, etoposide phosphate is completely converted to etoposide in plasma. Etoposide is metabolized by opening of the lactone ring, O-demethylation, and conjugation (i.e., glucuronidation and sulfation). O-demethylation occurs through the CYP450 3A4 isoenzyme pathway to produce the active catechol metabolite.

Excretion

At 120 hours after intravenous administration of radiolabeled etoposide formulation, the mean recovery of radioactivity in the urine was 56% of the dose, 45% of which was excreted as etoposide and 8% or less as metabolites. Fecal recovery of radioactivity was 44% of the dose.

Specific Populations

Following intravenous administration of etoposide in adults, the total body clearance of etoposide was correlated with creatinine clearance, serum albumin concentration, and non-renal clearance. No clinically significant differences in the pharmacokinetics of etoposide were observed based on age and sex.

Drug Interaction Studies

Cisplatin: Co-administration of cisplatin may increase exposure to etoposide.

Highly protein-bound drugs: Phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide in vitro.

Select antiepileptic medications: Co-administration with antiepileptic medications including phenytoin, phenobarbital, carbamazepine, and valproic acid may increase etoposide clearance.

Etoposide may be a substrate of the P-glycoprotein (P-gp) transporter system based upon in vitro studies.

Clinical Studies

Study 1 was a multicenter trial in patients, with previously untreated, small cell lung cancer, randomized (1:1) to receive either etoposide phosphate (80 mg/m2 /day) plus cisplatin (20 mg/m2 /day) for 5 days, or etoposide (80 mg/m2 /day) plus cisplatin (20 mg/m2 /day). The major efficacy outcome measure was objective response rate (ORR).

Among the 121 patients enrolled, the median age was 64 years, 65% of patients were male, 89% were White, and ECOG performance score was 0 to 2.

Study 1 demonstrated an overall response rate of 61% (95% confidence interval [CI] 47, 73) for patients treated with etoposide phosphate plus cisplatin, and 58% (95% CI: 45, 71) for those receiving etoposide plus cisplatin.

Last reviewed on RxList: 4/28/2017
This monograph has been modified to include the generic and brand name in many instances.

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