Summary
This report describes an unexpected adverse effect in three children receiving teniposide at 3–5 times the conventional dosage (i.e. 200 mg/m2) plus cytarabine as part of continuation therapy for acute lymphocytic leukemia. Pharmacokinetic studies in each patient had demonstrated high teniposide clearances, and thus the increased dosage requirements were necessary to attain plasma concentrations similar to those expected for patients with average drug clearance. At 3–4 h after the beginning of the 4-h simultaneous infusions of teniposide and cytarabine, these patients experienced somnolence, hypotension, and metabolic acidosis. The adverse events were associated with elevated teniposide plasma concentrations during the infusions compared with those in patients receiving similar doses without toxicity, and clinically significant ethanol concentrations, presumably from the teniposide formulation. Blood concentrations of cremophor and histamine, which are also constituents of the teniposide formulation, were not measured. In addition, concomitant therapy with antiemetic agents in patients who may have been mildly volume-depleted due to emesis may also play a contributory role. Prolonging the infusion time for patients receiving teniposide doses above 500 mg/m2 will avoid excessive teniposide and ethanol plasma concentrations and minimize the risk of this potentially serious side effect.
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Chapuis B, Helg C, Jeannet M, Zulian G, Huber P, Gumovski P (1985) Anaphylactic reaction to intravenous cyclosporine. N Engl J Med 312: 1259
De Marchi S, Cecchin E (1986) Ethanol-induced water diuresis: one of a spectrum of renal defects resulting from ethanol toxicity. Nephron 43: 79
De Marchi S, Cecchin E, Grimaldi F, Basile A (1984) Alcohol and renal function. Ann Intern Med 101: 145
Gaudy JH, Sicard JF, Lhoste F, Boitier JF (1987) The effects of cremophor EL in the anaesthetized dog. Can J Anaesth 34: 122
Grem JL, Hoth DF, Leyland-Jones B, King SA, Ungerleider RS, Wittes RE (1988) Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases. J Clin Oncol 6: 351
Hartmann D, Fluckiger A, Ziegler WH, Timm U, Zell M (1988) Experimental model for the investigation of kinetic and/or dynamic interactions between drugs and ethanol in humans. J Pharm Sci 77: 299
Heinemann V, Estey E, Keating MJ, Plunkett W (1989) Patient specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. J Clin Oncol 7: 622
Kellie SJ, Crist WM, Pui C-H, Crone ME, Fairclough DL, Rodman JH, Rivera GK (1991) Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia. Cancer 67: 1070
Litovitz T (1986) The alcohols: ethanol, methanol, isopropanol, ethylene glycol. Pediatr Clin North Am 33: 311
Lorenz W, Schmal A, Schult H, Lang S, Ohmann C, Weber D, Kapp B, Luben L, Doenicke A (1982) Histamine release and hypotensive reactions in dogs by solubilizing agents and fatty acids: analysis of various components in cremophor EL and development of a compound with reduced toxicity. Agents Actions 12: 64
Magalini SC, Nanni G, Agnes S, Citterio F, Castagneto M (1986) Anaphylactic reaction to first exposure to cyclosporine. Transplantation 42: 443
Milner G, Landauer A (1971) Alcohol, thioridazine, and chlorpromazine effects on skills related to driving behavior. Br J Psychiatr 118: 351
National Cancer Institute (1988) Cancer therapy evaluation program: reporting of adverse drug reactions. (NCI Division of Cancer Treatment Guidelines) NCI, Bethesda Md.
O'Dwyer PJ, King SA, Fortner CL, Leyland-Jones B (1986) Hypersensitivity reactions to teniposide (VM-26): an analysis. J Clin Oncol 4: 1262
Pohorecky LA (1985) Ethanol diuresis in rats: possible modifying factors. J Pharm Pharmacol 37: 271
Puddey IB, Vandongen R, Beilin LJ, and Rouse IL (1985) Alcohol stimulation of renin release in man: its relation to the hemodynamic, electrolyte, and sympatho-adrenal responses to drinking. J Clin Endocrinol Metab 61: 37
Rivera G (1988) The epipodophyllotoxin teniposide in therapy for childhood acute lymphocytic leukemia. J Clin Oncol 6: 191
Rodman JH, Ambromowitch M, Sinkule JA, Hayes FA, Rivera GK, Evans WE (1987) Clinical pharmacodynamics of teniposide: systemic exposure as a determinant of response. J Clin Oncol 7: 1007
Rodman JH, Sunderland M, Kavanagh RL, Ochs J, Yalowich J, Evans WE, Rivera GK (1990) Pharmacokinetics of continuous infusion methotrexate and teniposide. Cancer Research 50: 4267
Saario I (1976) Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol. Ann Clin Res 8: 117
Sinkule JA, Evans WE (1983) High-performance liquid chromatographic assay for cytosine arabinoside, uracil arabinoside and some related nucleosides. J Chromatogr 274: 87
Sinkule JA, Evans WE (1984) High-performance liquid chromatographic analysis of the semisynthetic epipodophyllotoxin teniposide and etoposide using electrochemical detection. J Pharm Sci 73: 164
Stoelting RK (1983) Allergic reactions during anesthesia. Anest Analg 62: 341
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The work described in this paper was supported by: Leukemia Program Project grant CA20 180, CORE Cancer Center Support grant CA21 765, a Center of Excellence grant from the State of Tennessee, and American Lebanese Syrian Associated Charities (ALSAC)
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McLeod, H.L., Baker, D.K., Pui, CH. et al. Somnolence, hypotension, and metabolic acidosis following high-dose teniposide treatment in children with leukemia. Cancer Chemother. Pharmacol. 29, 150–154 (1991). https://doi.org/10.1007/BF00687326
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DOI: https://doi.org/10.1007/BF00687326