Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer

• Published in: Journal of clinical oncology Vol. 32; no. 22; pp. 2328 - 2334
• Main Authors: INNOCENTI, Federico, SCHILSKY, Richard L, KARRISON, Theodore, MAITLAND, Michael L, SALGIA, Ravi, RATAIN, Mark J, RAMIREZ, Jacqueline, JANISCH, Linda, UNDEVIA, Samir, HOUSE, Larry K, DAS, Soma, KEHUA WU, TURCICH, Michelle, MARSH, Robert
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 01-08-2014
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Dose-Response Relationship, Drug; Faze; Genotype; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Humans; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; ORIGINAL REPORTS; Tumors; Camptothecin derivatives; Antineoplastic agent; Human; Typing; Enzyme; DNA topoisomerase; Enzyme inhibitor; Genotype; Malignant tumor; Posology; Irinotecan; Isomerases; Cancerology; Pharmacokinetics; Topoisomerase I inhibitor; Dose; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2014.55.2307

The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes.
Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1.
In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r(2) = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r(2) = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response.
The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.