Etoposide phosphate

Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate. Proc. Natl. Acad. Sci. USA 85, 4842. 

Another promising prodrug undergoing clinical evaluation is etoposide phosphate. Here, the phenolic group of this chemically complex antitumor... 

Podophyllotoxin (3) is a precursor to the three cUnically used anticancer drugs, etoposide (4), teniposide (5), and etoposide phosphate (6). Its mechanism of action involves inhibition of tubuUn polymerization and disruption of mitosis during metaphase of the cell cycle. Both etoposide and teniposide are modifications of podophyllotoxin specifically designed to increase the water solubility, reduce gastric toxicity in addition to inhibiting topoisomerase II, and disrupting the cell cycle. 

Senter, P. D., Saulnier, M. G., Schreiber, G. J., Hirschberg, D. L., Brown, J. P., Hellstrom, I., and Hellstrom, K. E. (1988) Anti-tumor effects of antibody—alkaline phosphatase conjugates in combination with etoposide phosphate. Proc. Natl. Acad. Sci. U.S.A. 85, 4842. 

Sessa, C., et al. 1995. Phase I clinical and pharmacokinetic study of oral etoposide phosphate. J Clin Oncol 13 200. 

Amsacrine Aclarubicin Carboplatin Etoposide phosphate Asparaginase... 

A 52-year-old patient with glioblastoma developed severe ocular and orbital toxicity after receiving intracarotid etoposide phosphate and carboplatin (268). Acutely non-pupiUary block angle-closure glaucoma developed secondary to uveal effusion in the ipsilateral eye. Four days later, severe orbital inflammation resulted in reduced visual acuity, proptosis, optic neuropathy, and total external ophthalmoplegia. 

Lauer AK, Wobig JL, Shults WT, Neuwelt EA, Wilson MW. Severe ocular and orbital toxicity after intracarotid etoposide phosphate and carboplatin therapy. Am J Ophthalmol 1999 127(2) 230-3. 

At low doses of oral etoposide (for example 50-100 mg), the systemic availability averages 66%, and at higher dosages (100 mg/m and over) 47%. If etoposide phosphate is used, the values are higher (range 66-84%) (68-73). 

After intravenous administration of etoposide 150 mg/ m, the peak plasma concentration averages 20 micro-grams/ml and the half-life 7.1 hours. Drug clearance and distribution volume are about 16 ml/minute/m and 17 1/ m (6,7,74). With respect to plasma concentrations of etoposide, intravenous etoposide phosphate is equivalent to intravenous etoposide with conventional or intensified dose schedules (75-79). After intravenous administration, the prodrug etoposide phosphate undergoes rapid hydrolysis catalysed by alkaline phosphatase this conversion is linear even at high intravenous doses of 1200 mg/m infused over 2 hours on days 1 and 2. 

In contrast, the structurally related etoposide phosphate is highly soluble in aqueous solutions and no solubilizing adjuvants are necessary. Preliminary data suggest that the incidence of hypersensitivity reactions is lower with etoposide phosphate than with etoposide, strengthening the hypothesis that adjuvants have a major role in the development of allergic reactions (123,124). In one case, a patient who had a type I hypersensitivity reaction to etoposide was successfully retreated with etoposide phosphate (134). 

Successful rechallenge has been reported after a reaction to etoposide in a 19-year-old man, who was successfully re-treated with etoposide phosphate with only antiemetic doses of glucocorticoids as cover (134). This case tends to support the old assumption that etoposide hypersensitivity is due to the excipients in the formulation. 

Chabot GG, Armand JP, Terret C, de Fomi M, Abigerges D, Winograd B, Igwemezie L, Schacter L, Kaul S, Ropers J, Bonnay M. Etoposide bioavailability after oral administration of the prodrug etoposide phosphate in cancer patients during a phase I study. J Clin Oncol 1996 14(7) 2020-30. 

Schacter LP, Igwemezie LN, Seyedsadr M, Morgenthien E, Randolph J, Albert E, Santabarbara P. Clinical and pharmacokinetic overview of parenteral etoposide phosphate. Cancer Chemother Pharmacol 1994 34(Suppl) S58-63. 

Kaul S, Igwemezie LN, Stewart DJ, Fields SZ, Kosty M, Levithan N, Bukowski R, Gandara D, Goss G, O Dwyer P, Schacter LP, Barbhaiya RH. Pharmacokinetics and bioequivalence of etoposide following intravenous administration of etoposide phosphate and etoposide in patients with solid tumors. J Clin Oncol 1995 13(11) 2835-41. 

Budman DR, Igwemezie LN, Kaul S, Behr J, Lichtman S, Schulman P, Vinciguerra V, Allen SL, Kolitz J, Hock K, O Neill K, Schacter L, Barbhaiya RH. Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with sohd tumors. J Clin Oncol 1994 12(9) 1902-9. 

Reif S, Kingreen D, Kloft C, Grimm J, Siegert W, Schunack W, Jaehde U. Bioequivalence investigation of high-dose etoposide and etoposide phosphate in lymphoma patients. Cancer Chemother Pharmacol 2001 48(2) 134-40. 

Kreis W, Budman DR, Vinciguerra V, Hock K, Baer J, Ingram R, Schacter LP, Fields SZ. Pharmacokinetic evaluation of high-dose etoposide phosphate after a 2-hour infusion in patients with solid tumors. Cancer Chemother Pharmacol 1996 38(4) 378-84. 

Bernstein BJ, Troner MB. Successful rechallenge with etoposide phosphate after an acute hypersensitivity reaction to etoposide. Pharmacotherapy 1999 19(8) 989-91. 

Siderov J, Prasad P, De Boer R, Desai J. Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide. Br J Cancer 2002 86(1) 12-13. 

Myelosuppression mucositis worse with continuous infusion moderately emetogenic may cause acute and delayed (by 24 8 hours) emesis vesicant severe extravasation injury cardiotoxicity (similar to other anthracyclines) may be less cardiotoxic than doxorubicin controversy about equ ivalent doses cardiac toxicity associated with cumulative doses >900 mg/m Myelosuppression moderately emetogenic may be worse with oral and high-dose regimens alopecia mucositis hypotension infusion rate-related etoposide phosphate can be given IV push without hypotension risk hypersensitivity reactions especially common in children... 

Junghanss C, Leithauser M, Wilhelm S et al. (2001). High-dose etoposide phosphate and G-CSF mobilises peripheral blood stem cells in patients that previously failed to mobilise. Ann Hematol, 80,96-102. 

Igwemezie, L.N. Kaul, S. Barbhaiya, R.H. Assessment of toxicokinetics and toxicodynamics following intravenous administration of etoposide phosphate in beagle dogs. Pharm.Res., 1995, 12, 117-123... 

Ragozina, N. Y, Putz, M., Heissler, S., Faubel, W., and Pyell, U., Quantification of etoposide and etoposide phosphate in humanplasmaelectrokineticby micellar chromatography and near-field thermal... 

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