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- Title
Prophylaxis of Irinotecan-Induced Diarrhea with Neomycin and Potential Role for UGT1A1*28 Genotype Screening: A Double-Blind, Randomized, Placebo-Controlled Study.
- Authors
DE JONG, FLORIS A.; KEHRER, DIEDERIK F. S.; MATHIJSSEN, RON H. J.; CREEMERS, GEERT-JAN; DE BRUIJN, PETER; VAN SCHAIK, RON H. N.; PLANTING, ANDRÉ S. TH.; VAN DER GAAST, ATE; ESKENS, FERRY A. L. M.; JANSSEN, JOS TH. P.; RUIT, JAN B.; VERWEIJ, JAAP; SPARREBOOM, ALEX; DE JONGE, MAJA J. A.
- Abstract
Objective. Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea. Patients and Methods. Patients were treated with irinotecan in a multicenter, double-blind, randomized, placebo-controlled trial. Eligible patients received irinotecan (350 mg/m² once every 3 weeks) combined with neomycin (660 mg three times daily for three consecutive days, starting 2 days before chemotherapy) or combined with placebo. Blood samples were obtained for additional pharmacokinetic and pharmacogenetic analyses. Results. Sixty-two patients were evaluable for the toxicity analysis. Baseline patient characteristics, systemic SN-38 exposure, and UGT1A1*28 genotype status (i.e., an additional TA repeat in the promoter region of uridine diphosphate-glucuronosyltransferase isoform 1A1) were similar in both arms. Although distribution, severity, and duration of delayed-type diarrhea did not differ significantly between arms, grade 3 diarrhea tended to be less frequent in the neomycin arm. The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2-3 diarrhea. In the neomycin arm, grade 2 nausea was significantly more common. Conclusion. Our results do not suggest a major role for neomycin as prophylaxis for irinotecan-induced delayed-type diarrhea. It is suggested that the UGT1A1*28 genotype status could be used as a screening tool for a priori prevention of irinotecan-induced delayed-type diarrhea.
- Subjects
DIARRHEA; NEOMYCIN; PHARMACOKINETICS; PHARMACOGENOMICS; GLUCURONIDES
- Publication
Oncologist, 2006, Vol 11, Issue 8, p944
- ISSN
1083-7159
- Publication type
Article
- DOI
10.1634/theoncologist.11-8-944