The initial t1/2 is 1.5 hours and the mean terminal half -life is 4 to 11 hours. It is primarily excreted in the urine. 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/m2 or about 35% of the total body clear ance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and non renal processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the non renal clearance of etoposide. The maximum plasma concentration and area under the concentration time curve (AUC) exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins (~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide systemic exposure is related to toxicity. Preliminary data sugg ests that systemic exposure for unbound etoposide correlates better than total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. Cmax and AUC values for orally administered etoposide capsules consistently fall in the same range as t he Cmax and AUC values for an intravenous dose of one -half the size of the oral dose. The overall mean value of oral capsule bioavailability is approximately 50% (range 25- 75%). Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate that etoposide phosphate is bioequivalent to etoposide when it is administered in molar equivalent doses. Etoposide for Injection is available in sterile multiple dose vials. The pH of the clear, nearly colorless to yellow liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30mg benzyl alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened vials of Etoposide are stable until expiration date on package at room temperature (25°C). Etoposide phosphate for injection is available for intravenous infusion as a sterile lyophilized powder in single -dose vials containing etoposide phosphate equivalent to 100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide phosphate must be stored under refrigeration 2°-8°C (36°- 46°F). Unopened vials of etoposide phosphate are stable until the expiration date on the package. 3.6.2 Supplier Re-MATC H Protocol Page 71 of 106 Version: 20180628 Re-MATC H Protocol Page 72 of 106 Version: 20180628 18.5 Temozolomide (Temodar®) Chemical Name 3,4-dihydro -3-methyl- 4-oxoimidazo[5,1- d]-as-tetrazine -8-carboxamide1 TMZ is commercially available from Schering -Plough Research Institute under the trade name Temodar®. TMZ undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound, Maximally Tolerated Inhibitory Concentration (MTIC). The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) o ccurs primarily at the O6 and N7 positions of guanine. TMZ is available in capsules that are white in color with colored imprints indicating the different doses: 5 mg (green imprint), 20 mg (brown imprint), 100 mg (blue imprint) and 250 mg (black imprint) . Capsules should be stored at 25ºC (77ºF); excursions permitted to 15- 30ºC (59- 86ºF). The commercial product has an expiration date on the bottle. TMZ will be administered orally, 30 minutes following the completion of each O6- Benzylguanine infusion. I f a patient has emesis within 10 minutes of receiving a dose, the dose should be repeated as soon as the patient is able to tolerate re- dosing. If a patient cannot tolerate re- dosing within 2 hours of completion of the O6- Benzylguanine infusion, or has rep eated emesis, no further doses of TMZ will be given on that day. For patients unable to swallow intact capsules, capsules may be opened and mixed with apple juice or applesauce, or administered via Gastronomy Tube (G -Tube) or Nasogastric Tube (NG -tube.) If mixing capsule contents with apple juice or apple sauce is necessary, mix the contents immediately prior to administration. Care must be taken to avoid inhaling the powder or having the powder come in contact with skin or mucous membranes.