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Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid Tumors

From the Departments of Hematology-Oncology, Pharmaceutical Sciences, Biostatistics, and Molecular Pharmacology, St Jude Children's Research Hospital; Departments of Pharmacy and Pharmaceutical Sciences, College of Pharmacy, and Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN; and Miami Children's Hospital, Miami, FL

Address reprint requests to Wayne L. Furman, MD, Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794l; e-mail: wayne.furman{at}stjude.org

PURPOSE: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea.

PATIENTS AND METHODS: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m²/d without cefixime and then from 45 to 60 and 75 mg/m²/d with cefixime.

RESULTS: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m²/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m²/d without cefixime but 60 mg/m²/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ngxh/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030).

CONCLUSION: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Supported by Grants No. CA23099 and CA21765 from the National Institutes of Health, by a grant from the Pharmacia UpJohn and Pfizer corporations, and by the American Lebanese Syrian Associated Charities.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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