Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2014 Aug 1;32(22):2328-34.
doi: 10.1200/JCO.2014.55.2307. Epub 2014 Jun 23.

Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer

Federico Innocenti  1 , Richard L Schilsky  2 , Jacqueline Ramírez  2 , Linda Janisch  2 , Samir Undevia  2 , Larry K House  2 , Soma Das  2 , Kehua Wu  2 , Michelle Turcich  2 , Robert Marsh  2 , Theodore Karrison  2 , Michael L Maitland  2 , Ravi Salgia  2 , Mark J Ratain  2
Affiliations
Clinical Trial

Dose-finding and pharmacokinetic study to optimize the dosing of irinotecan according to the UGT1A1 genotype of patients with cancer

Federico Innocenti et al. J Clin Oncol. .

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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.

Conclusion: 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.

PubMed Disclaimer

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
Relationship between the UGT1A1*28 genotype and dose-adjusted areas under the curve (AUCs) of irinotecan (A; P = .62) and SN-38 (B; P = .01). Horizontal bars represent the means.
Fig 2.
Fig 2.
Area under the curve (AUC) of irinotecan (A; r2 = 0.39; P < .001) and SN-38 (B; r2 = 0.0003; P = .97) at the maximum-tolerated dose (MTD) for each genotype. Horizontal bars represent the means.
See this image and copyright information in PMC

Comment in

References

    1. Meyerhardt JA, Mayer RJ. Systemic therapy for colorectal cancer. N Engl J Med. 2005;352:476–487. - PubMed
    1. Innocenti F, Ratain MJ. Pharmacogenetics of irinotecan: Clinical perspectives on the utility of genotyping. Pharmacogenomics. 2006;7:1211–1221. - PubMed
    1. Ramchandani RP, Wang Y, Booth BP, et al. The role of SN-38 exposure, UGT1A1+28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol. 2007;47:78–86. - PubMed
    1. Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22:1382–1388. - PubMed
    1. Minami H, Sai K, Saeki M, et al. Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: Roles of UGT1A1+6 and +28. Pharmacogenet Genomics. 2007;17:497–504. - PubMed

Publication types

MeSH terms

LinkOut - more resources