Objective. Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterialmediated 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/m 2 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 irinotecaninduced 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 delayedtype diarrhea. The Oncologist 2006;11:944-954
PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m2 intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m2) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography. RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P = .002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P = .004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P = .90) and formation of SN-38G (P = .93). CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.
The topoisomerase I inhibitors reviewed in this paper are all semisynthetic analogs of camptothecin (CPT). Modulation of this intranuclear enzyme translates clinically in to antitumor activity against a broad spectrum of tumors and is therefore the subject of numerous investigations. We present preclinical and clinical data on CPT analogs that are already being used in clinical practice [i.e. topotecan and irinotecan (CPT-11)] or are currently in clinical development (e.g. 9-aminocamptothecin, 9-nitrocamptotecin, lurtotecan, DX 8951f and BN 80915), as well as drugs that are still only developed in a preclinical setting (silatecans, polymer-bound derivates). A variety of different strategies is being used to modulate the systemic delivery of this class of agents, frequently in order to increase antitumor activity and/or reduce experienced side effects. Three principal approaches are discussed, including: (i) pharmaceutical modulation of formulation vehicles, structural alterations and the search for more water-soluble prodrugs, (ii) modulation of routes of administration and considerations on infusion duration, and (iii) both pharmacodynamic and pharmacokinetic biomodulation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.