Abstract
An autologous bone marrow transplant regimen of ifosfamide, carboplatin, and etoposide (ICE) has been developed as treatment for certain malignancies. At maximum tolerated doses renal insufficiency precludes dose escalation. The objective was to examine whether measurement of plasma drug levels early during treatment would provide warning of renal failure. Nine patients received a 96-h continuous infusion of ifosfamide 16000 mg/m2, carboplatin 1600 mg/m2, and etoposide 1200 mg/m2. Pharmacokinetics, including drug levels and plasma concentration-time curves, of ifosfamide, ultrafiltrable platinum (uPt) and etoposide were analyzed and correlated with renal function. One of the nine patients developed anuric renal failure requiring hemodialysis. By 17 h from the start of infusion, this patient showed substantially higher drug levels of ifosfamide (200 vs mean 217 μM) and uPt (19 vs mean 10μM) than those patients with preserved renal function. The 95% confidence intervals suggested that a 16–22 h ifosfamide level >153 μM and an uPt level >μM predict the development of significant renal dysfunction. Although drug levels were substantially higher at 56 h, the serum creatinine did not yet reflect kidney injury. This study suggests that high plasma ifosfamide and uPt levels, analyzed early in the course of a 96-h infusion of high-dose ICE, provide warning of severe and potentially fatal renal injury. Since ICE has substantial activity in a number of malignancies, but significant renal morbidity, real-time pharmacokineticguided dosing may reduce treatment-related toxicity.
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Supported in part by US. Public Health Service Grants PO1-CA-38493 and CA-06516 and a grant from the Mathers Foundation. Drs. Ayash and Schwartz are recipients of a Career Development Award from the American Cancer Society
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Wright, J.E., Elias, A., Tretyakov, O. et al. High-dose ifosfamide, carboplatin, and etoposide pharmacokinetics: correlation of plasma drug levels with renal toxicity. Cancer Chemother. Pharmacol. 36, 345–351 (1995). https://doi.org/10.1007/BF00689053
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DOI: https://doi.org/10.1007/BF00689053