Study Identifies Irinotecan Dosing Levels Based on UGT1A1 Genotype
Risk of severe irinotecan-associated neutropenia is related in part to presence of the UGT1A1*28 variant, which is linked to reduced elimination of the irinotecan active metabolite SN-38. In a study reported in the Journal of Clinical Oncology, Innocenti et al identified appropriate irinotecan dosing levels according to UGT1A1*28 genotype.
In the study, 46 patients with advanced solid tumors received a flat dose of IV irinotecan every 3 weeks; 46% had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the*28/*28 genotype. Starting doses of irinotecan were 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype.
Genotype-Related Maximum Tolerated Doses
In patients with the *1/*1 genotype, the maximum tolerated dose was 850 mg, with four dose-limiting toxicities observed in 16 patients at this dose level; 1,000 mg was not tolerated, with two dose-limiting toxicities observed in six patients. In patients with the *1/*28 genotype, the maximum tolerated dose was 700 mg, which was associated with five dose-limiting toxicities in 22 patients; 850 mg was not tolerated, resulting in four dose-limiting toxicities in six patients. In patients with the *28/*28 genotype, the maximum tolerated dose was 400 mg, producing one dose-limiting toxicity in six patients, and 500 mg was not tolerated, producing three dose-limiting toxicities in three patients. Dose-limiting toxicities consisted primarily of myelosuppression and diarrhea.
Genotype-Related SN-38 Kinetics
Irinotecan clearance followed linear kinetics over the 400 to 1,000 mg dose range. Dose-adjusted irinotecan area under the concentration-time curve (AUC) was independent of the UGT1A1*28 genotype (P= .62), whereas dose-adjusted SN-38 AUC was increased in patients with the *1/*28 or *28/*28 genotype vs those with the *1/*1 genotype (P = .01). At the maximum tolerated dose for each genotype, dosing according to genotype resulted in similar SN-38 AUCs (r2 = .0003, P = .97), whereas the irinotecan AUC was correlated with irinotecan dose (r2 = .39, P < .001).
Four partial responses were observed in 48 evaluable patients; responses occurred in one patient with non–small cell lung cancer with the *1/*28 genotype at a dose of 700 mg, one with gastric cancer and the *1/*1 genotype at 850 mg, one with small bowel cancer and the *1/*28 genotype at 850 mg, and one with small cell lung cancer and the *1/*1 genotype at 850 mg.
The investigators concluded, “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.”
Federico Innocenti, MD, PhD, of University of North Carolina at Chapel Hill, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from PAAR-Pharmacogenomics of Anticancer Agents Research Group, National Institute of General Medical Sciences, The University of Chicago Comprehensive Cancer Center, and National Cancer Institute. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
