No abstract

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.