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document
Phase I pharmacokinetic , food effect , and pharmacogenetic study of oral irinotecan given as semisolid matrix capsules in patients with solid tumors . PURPOSE To characterize the maximum-tolerated dose , recommended dose , dose-limiting toxicities ( DLT ) , pharmacokinetic profile , and food effect of orally administered irinotecan formulated as new semisolid matrix capsules . EXPERIMENTAL DESIGN Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks . Patients were randomly assigned to take the drug along with a high-fat , high-calorie breakfast for the administration at day 1 of the first or second cycle . Dosages tested were 70 and 80 mg/m ( 2 ) /day . RESULTS Twenty-five patients received 101 cycles of therapy ( median two cycles , range 1-15 ) . During the first cycle , grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m ( 2 ) /day in three out of five patients . Hematologic and nonhematologic toxicities were mild to moderate . Exposure to the active metabolite SN-38 was relatively high compared with i.v . infusion , but no relevant accumulation was observed . Food had no significant effect on irinotecan pharmacokinetics . One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients . No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity . CONCLUSIONS For oral irinotecan , a dose of 70 mg/m ( 2 ) /day for 5 consecutive days every 3 weeks is recommended for further studies . Delayed diarrhea was the main DLT , similar to that observed with intravenously administered irinotecan . This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics .
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Intervention_Pharmacological
irinotecan
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Intervention_Pharmacological
irinotecan
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Intervention_Pharmacological
Irinotecan
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Intervention_Other
high-fat , high-calorie breakfast
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Intervention_Pharmacological
irinotecan
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Intervention_Pharmacological
irinotecan
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Intervention_Pharmacological
irinotecan
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Outcome_Physical
grade 3 delayed diarrhea and grade 3 fever
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Outcome_Physical
Hematologic and nonhematologic toxicities
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Outcome_Other
Exposure to the active metabolite SN-38
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Outcome_Other
severe irinotecan-induced toxicity .