SOME WORDS ABOUT ALTRETAMINE AND ESTRAMUSTINE Classification: Nonclassic alkylating agent – Triazine derivative. Mechanism of action: • Requires biochemical activation in the liver for its antitumor activity. • Exact mechanism(s) of action is unclear but appears to act like an alkylating agent & forms cross-links with DNA resulting in inhibition of DNA synthesis & its function. • May also inhibit RNA synthesis. Mechanism of Resistance: • Mechanisms of resistance have not been well characterized. • Does not exhibit cross-resistance to other classic alkylating agents & does not exhibit multi-drug-resistant phenotype. Absorption: • Oral absorption is extremely variable secondary to extensive first-pass metabolism in the liver. • Peak plasma levels are achieved 0.5 – 3 hours after an oral dose. Distribution: • Widely distributed throughout the body, with highest concentrations found in tissues with high fat content. • About 90% of drug is bound to plasma proteins. Metabolism: • Extensively metabolized in the liver by the microsomal P 450 system. • < 1% of parent compound is excreted in urine. • About 60% of drug is eliminated in urine as dimethylated metabolites within the first 24 hours. • The terminal elimination half-life is on the order of 4 – 10 hours. Indications: Ca. Ovary – advanced / recurrent – particularly in tumors that are resistant to alkylating agents / taxens. Dose: 260 mg / m2 / day PO – in 4 dd after meals & at bed time X 14 or 21 days q d 28 . Drug preparation: 50 mg gelatin capsules. Drug interaction: • Cimetidine increases the half-life & subsequent toxicity . • Phenobarbital decreases the half-life & toxicity. • Concurrent use of MAO inhibitors may result in significant orthostatic hypotension. Side effects: • Nausea / Vomiting – worsen with cumulative doses – dose limiting. • Myelosupression – dose limiting. WBC & Platelet nadirs occur at 3-4 weeks with recovery by day 28. Anemia occurs in 20% of patients. • Neurotoxicity in the form of somnolence, mood changes, lethargy, depression, agitation, hallucinations & peripheral neuropathy – observed in about 25% of patients. • Hypersensitivity skin rash. • Elevation in LFTs – mainly SAP. • Flu-like syndrome in the form of fever, malaise, arthralgias & myalgias. • Abdominal cramps & diarrhea – occasional. Special considerations: • Closely monitor patients for neurologic toxicity. • Vitamin B 6 (Pyridoxine) may be used to decrease nurologic toxicity which may compromise anti-tumor activity. • Pregnancy category D ESTRAMUSTINE Classification: • Antimicrotubule agent. • Conjugate of nor-nitrogen mustard & estradiol phosphate. • Cell cycle-specific agent with activity in the M-phase. Mechanism of action: • Initially designed to target cancer cells expressing estrogen receptors. However, it is active against estrogen receptor-negative tumor cells. • Although this compound was initially designed as an alkylating agent, it has no alkylating activity. • Inhibits microtubule structure & function and the process of microtubule assembly by binding to microtubule-associated proteins (MAPs). Mechanism of Resistance: • Mechanisms of cellular resistance are different from those identified for other antimicrotubular agents. • Estramustine-resistant cells do not express increased levels of P 170 glycoprotein & are not cross-reactant to other antimicrotubule agents & / or natural products. • Estramustine-resistant cells display increased efflux of drug with decreased drug accumulation – mechanism ill defined. Absorption: Highly bio-available – 70 to 75% of an oral dose is absorbed. Metabolism: • Supplied as the estramustine phosphate form which renders it more water-soluble. • Rapidly dephosphorelated in the GI tract so that the dephosphorelated form predominates about 4 hours after ingestion. • Metabolized primarily in liver. • About 15 – 20 % of the drug of the drug is excreted in urine. • Only small amounts of un-metabolized drug are found. • Biliary & fecal excretion of alkylating & estrogenic metabolites has also been demonstrated. • Prolong half-life: 20 – 24 hours. Indications: Hormone-refractory, metastatic prostate cancer. Dose: 1. Single agent: 14 mg / kg / day PO in 3-4 dd. | Assessed after 30 – 90 days. | Can be given for months / years. 2. CCT: A. VINBLASTINE-ESTRAMUSTINE: (1999) Vinblastine – 4 mg / m 2 IV bolus weekly X 6 wks: 2 wk off. Estramustine – 600 mg / m 2 PO d 1 – 42 , rpt every 8 weeks. B. DOCETAXEL – ESTRAMUSTINE: (2001) Docetaxel – 70 mg / m 2 IV on d 2. Estramustine – 10 mg / m 2 PO tid on d 1 – 5. Dexamethasone – 8mg bid d 1 – 3 , starting 24 hours before Docetaxel. --- to be repeated every 21 days. C. PACLITAXEL-ESTRAMUSTINE: (2002) Paclitaxel – 150 mg / m 2 IV on d 2, 9, 16. Estramustine – 280 mg PO tid on d 1-3, 8-10, 15-17. --- to be repeated every 28 days. D. PACLITAXEL-ESTRAMUSTINE-CARBOPLATIN: (2002) Paclitaxel – 100 mg / m 2 IV weekly. Estramustine – 10 mg / kg PO daily. Carboplatin – AUC – 6 IV on d 1. -- to be repeated every 28 days. Drug preparation: 140 mg capsule. Drug interactions: • Estramustine phosphate reduces the systemic clearance of docetaxel and paclitaxel, most likely by inhibiting the effects of estramustine on the P-450 CYP3A4 isoenzyme, which is principally responsible for taxane clearance. • Therefore, the recommended doses of docetaxel and paclitaxel in combination with estramustine phosphate are less than single-agent doses, despite the fact that the taxanes and estramustine phosphate do not have common toxicities. Side effects: • Nausea & vomiting – occur within 2 hours of ingestion. Usually mild & respond to antiemetic therapy. However, intractable vomiting may occur after 6-8 wks of therapy. • Gynecomastia – up to 5% of patients. Can be prevented by prophylactic breast irradiation. • Diarrhea – 15 to 25 % of patients. • Cardiac complications – rare. CCF, IHD & thromboembolism. • Myelosupression – rare. • Skin rash. Special precaution: • Instruct patients that milk, milk products & calcium-rich foods may impair absorption of drug. • Instruct patients to take estramustine with water 1 hour before meals or 2 hours after meals to decrease the risk of GI upset. • Administer prophylactic antiemetics to avoid nausea & vomiting. Contraindication: • With known hypersensitivity to estradiol or nitrogen mustard. • With peptic ulcer disease, severe liver disease or cardiac disease. Not given in patients with active throbophlebituis or thromboembolic disorders. Close monitoring is necessary in patients with history of IHD & / or stroke.
Posted on: Sun, 15 Sep 2013 08:10:17 +0000
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