Irinotecan pharmacokinetics/pharmacodynamics and UGT1A genetic polymorphisms in Japanese: roles of UGT1A1*6 and *28

Abstract

The haplotypes significantly associated with reduced area under concentration curve ratios and neutropenia contained UGT1A1*6 or *28, and both of them should be genotyped before irinotecan is given to Japanese and probably other Asian patients.

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

“…Earlier studies have shown that the UGT1A1*6 and UGT1A1*28 alleles are mutually exclusive 26,27 and contribute additively to the activity of UGT1A1 in Japanese subjects. 28 Subjects who were not homozygotes for the UGT1A1*6 allele and whose serum total bilirubin level showed a relatively high value could be carriers of one or two UGT1A1*28 alleles.…”

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

“…Of the drugegene pairs in Table 1, the pharmacogenomic relationships between irinotecan and UGT1A1 (for neutropenia risk) (Innocenti and Ratain, 2006), and 6-mercaptopurine/thioguanine and TPMT (for severe myelosuppression) (Relling et al, 2011) have the most consistent, strong supporting evidence in favor of their routine use. For UGT1A1 as an example, several prospective studies have demonstrated that patients with the high-risk genotypes (UGT1A1*28 and UGT1A1*6) are significantly more likely to experience neutropenia, with two of these studies corroborating the relationship with pharmacokinetic supportive data (Innocenti et al, 2004;Minami et al, 2007). In the largest such study of 250 metastatic colorectal cancer patients, the odds ratio of risk of cycle 1 grade 3 or 4 neutropenia was w9, although the relationship did not persist for subsequent cycles (Toffoli et al, 2006).…”

Pharmacogenetics and biomarkers in colorectal cancer

“…[94][95][96][97] The incidence of this polymorphism is much lower in patients of Asian origin. 97,98 Treatment of UGT1A1*28 patients with irinotecan results in reduced metabolism and increased accumulation of the active SN-38 compound and subsequently to higher risk of myelosuppression and diarrhea, as shown in a few prospective studies. 96,99 On the basis of this evidence, the Food and Drug Administration of the United States approved the use of the UGT1A1* 28 genotype test in 2005 and recommended a lower starting dose of irinotecan in patients with the homozygous variant.…”