Study on the Optimal Dose of Irinotecan for Patients with Heterozygous Uridine Diphosphate-Glucuronosyltransferase 1A1 (<i>UGT1A1</i>)

Abstract

Uridine 5′-diphospho-glucuronosyltransferase (UGT), a metabolic enzyme of irinotecan active metabolite, has two genetic polymorphisms (UGT1A1*6 and UGT1A1*28). In UGT1A1 homozygous or heterozygous patients, metabolism is delayed and the risk of developing adverse effects is increased, and therefore, dose reduction of irinotecan is considered. However, the specific dose reduction rate of irinotecan for heterozygous patients is uncertain. We studied the necessity of irinotecan dose reduction and its optimal dose in UGT1A1 heterozygous patients with lung cancer. Patients with lung cancer treated with irinotecan in the Tokushima University Hospital or Tokushima Municipal Hospital were included in this study. The dose of irinotecan was evaluated based on the relative dose intensity (RDI). The time to treatment failure (TTF) was defined as the period until treatment change, death, or progressive disease based on response evaluation criteria of solid tumors. We targeted 31 patients treated with irinotecan: 12 wild types (WT), 14 heterozygotes, and 1 complex heterozygote and 4 homozygotes. There was no significant difference in the TTF, but the mean RDI during the entire treatment period was significantly different in the wild type (79%), heterozygous (62%), and complex heterozygous and homozygous groups (46%). In addition, the proportion of patients who completed treatment without dose reduction in the WT group tended to be higher than that in the other groups. For lung cancer patients with UGT1A1 heterozygote types who start irinotecan therapy, reducing the initial dose by approximately 20% might be a safer chemotherapy without decreasing the therapeutic effect.

UGT1A1 Gene Polymorphisms in Patients with Small Cell Lung Cancer Treated with Irinotecan-Platinum Doublet Chemotherapy and Their Association with Gastrointestinal Toxicity and Overall Survival

“…The association of UGT1A1*6 polymorphisms with severe diarrhea was evident in only patients with colorectal cancer but not in patients with lung cancer who received a lower irinotecan dose than the former. Konaka et al, based on a Japanese study (n = 31), suggested that among patients with UGT1A1 polymorphisms, a dose reduction of approximately 20% could lead to chemotherapy administration with lesser AEs but similar efficacy [25].…”

Considerations When Applying Pharmacogenomics to Your Practice

“…Therefore, consideration for testing should be given to DPYD for fluoropyrimidines, 20 TPMT and NUDT15 for thiopurines, 21 and UGT1A1 for irinotecan. 22 Additional situations in which pharmacogenomic tests may be particularly useful are unexplained sensitivities or toxicities with multiple drugs not otherwise explained by drug interactions. 23 Sometimes metabolic patterns can be initially detected by considering the metabolism of drugs and the problems (eg, efficacy/adverse effects) that the patient has had in the past.…”

“…60,62 Of note, several genes that are commonly tested for pharmacogenomic purposes are also associated with disease states. For example, G6PD genetic variants have implications for many drugs, and variants in this gene are known to cause glucose-6phosphate dehydrogenase deficiency, 63 and UGT1A1 variation affects irinotecan 22 and atazanvir 64 but also can result in Gilbert syndrome or Criger-Najjar syndrome. 65 For these and other genes associated with hereditary disorders, it is important for providers to be aware of the possibility of a secondary finding in addition to gaining information about drug metabolism so that the patient is appropriately counseled before testing.…”

Pharmacogenetics for severe adverse drug reactions induced by molecular‐targeted therapy

“…The use of pharmacogenetic testing in the clinical setting is still limited to a few drugs, but genetic testing is covered by insurance in the USA, Japan, and some other countries 7,10,11 . In Japan, only the aforementioned 2 genetic tests ( UGT1A1 and NUDT15 ) are covered by insurance to avoid or predict the likelihood of the patient developing severe ADRs in response to cancer treatment.…”