Association between UGT1A1 variant alleles and irinotecan-induced severe neutropenia

HSA would like to share with healthcare professionals information regarding the distribution of genetic variants of the enzyme uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) among the major ethnic groups in Singapore.UGT1A1 plays an important role in the drug metabolism of irinotecan. The genetic variants are associated with a higher risk of irinotecan-induced severe neutropenia.

Irinotecan is locally registered for the treatment of patients with advanced colorectal cancer and is marketed under the following tradenames Campto® (Pfizer), DBL irinotecan injection concentrate (Hospira) and Irinotel® (Fresenius Kabi). Common adverse events associated with irinotecan are diarrhoea, vomiting, nausea, and neutropenia.Irinotecan-induced neutropenia can be severe, occasionally leading to hospitalisation because of a significant risk of contracting life-threatening infections.

UGT1A1 variant alleles and their effect on irinotecan metabolism

Irinotecan is converted in the body to a metabolite called SN-38, which is 100 to 1000 times more potent than irinotecan itself.¹ SN-38 is inactivated primarily by UGT1A1which glucuronidates SN-38 to an inactive metabolite, SN-38G (Figure 1).UGT1A1 is the same enzyme that mediates bilirubin conjugation.Glucuronidating activity is reduced when variants of the UGT1A1 gene, UGT1A1*28 or UGT1A1*6 are present.UGT1A1*28 contains 7, rather than 6, thymine-adenine (TA) repeats in the UGT1A1 promoter region and reduces enzyme expression;UGT1A1*6 represents a nucleotide change from guanine (G) to adenine (A) that causes an amino acid change from glycine to arginine and lowers the enzyme's activity.² As a result, patients with these variants have higher blood levels of SN-38 after receiving the same dose of irinotecan.

Figure 1 Shown here is part of the complex metabolic pathway of irinotecan. CYP3A4/5 refers tp cytochrome P450 3A4 and 3A5. CES1/2 refers to carboxylesterases 1 and 2. UGT1A1 is the main enzyme that catalyses the conversion of SN-38 to SN-38G.

Polymorphisms in other UGT genes as well as ABCB1, ABCG2, ABCC2 and SLCO1B1 genes, which encode proteins involved in irinotecan transport, may also contribute to variation in irinotecan and SN-38 pharmacokinetics and severity of neutropenia, but the evidence is considerably less well developed than for UGT1A1*6 and *28.^3-8 No definitive clinical studies have been published yet on the impact of irinotecan dosage adjustment on response rate based on a patient's genotype.This is an active area of clinical research internationally.

Regulatory activities in other countries/regions

In 2005, the United States Food and Drug Administration (US FDA) amended the product label for Camptosar®, a brand of irinotecan used in the US, to warn of an increased risk of severe neutropenia among patients who are homozygous for UGT1A1*28.⁹ This decision was reached after reviewing data from several clinical trials that supported the conclusion of a greater risk of Grade 3 or 4 neutropenia in patients homozygous for UGT1A1*28. Their analysis also showed a correlation between plasma concentrations of SN-38 and the probability of experiencing severe neutropenia.¹⁰ Another meta-analysis of nine studies (821 subjects) from North America and Europe, published in 2007, confirmed a significant association between UGT1A1*28 genotype and severe neutropenia at doses greater than 150 mg/m², but no association was seen at lower doses (100-125 mg/m²).¹¹ In 2008, a clinical study from Taiwan demonstrated that patients who were either heterozygous or homozygous for UGT1A1*28 had a higher rate of neutropenic fever and grade 3 or 4 neutropenia.¹²

In Japan, the Pharmaceutical and Medical Devices Agency (PMDA) also examined the evidence for an association between UGT1A1 variants and neutropenia.The UGT1A1*28 variant is much less common in Japanese compared to Caucasians (Figure 2).On the other hand, UGT1A1*6 is not uncommon in Japanese, yet is absent in Caucasians (Figure 3).Clinical data obtained in Japanese who were given irinotecan doses ranging from 60 to 150 mg/m² demonstrated that patients who were homozygous for UGT1A1*6 or UGT1A1*28 or double heterozygotes (*6/*28) had a lower ability to inactivate SN-38.Furthermore, the rate of Grade 3 or 4 neutropenia was 80% in homozygotes or double heterozygotes, 24% for UGT1A1*6 or UGT1A1*28 heterozygotes and 14% without either UGT1A1*6 or UGT1A1*28.^13,14In 2008, PMDA updated its product label for irinotecan to alert prescribers of the association between increased risk of serious adverse events and UGT1A1*6 and *28 variants.¹⁵

Local Context

HSA has in consultation with the Pharmacogenetics Advisory Committee, reviewed the distribution of UGT1A1 variants in the three major ethnic groups of Singapore -- Chinese, Malay, and Indian using data from the National Cancer Centre^16,17 the National University Hospital,¹⁸ and the Singapore Genome Variation Project.¹⁹ Among Singapore Indians, the genotype distribution of the UGT1A1*28 variant is comparable to Caucasians (Figure 2), while among Singapore Chinese, the genotype distribution of the UGT1A1*6 variant is similar to Japanese (Figure 3).The prevalence of double heterozygotes (*6/*28) in Singapore is 6.9%, 1.2% and 2.9% in Chinese, Malays and Indians, respectively.¹⁸

In view of the available evidence of greater risk of irinotecan toxicity associated with UGT1A1*6 and UGT1A1*28 variants and its potential impact on our local population, the HSA Pharmacogenetics Advisory Committee has advised that the package inserts for irinotecan be updated.

Consequently, the package inserts of all irinotecan-containing products would be updated to include the following cautionary statements:
“The active metabolite of irinotecan, SN-38, is metabolized predominantly by UDP-glucuronosyltransferase (UGT). It has been reported that patients who are homozygous (UGT1A1*6/*6 or UGT1A1*28/*28) or heterozygous (UGT1A1*6/*28) in allele UGT1A1*6, UGT1A1*28 of UGT may be at increased risk for serious adverse reactions (especially neutropenia) caused by reduced glucuronidation of SN-38.Added caution should be exercised when administering in such patients.”

A genotyping test for UGT1A1*6 and UGT1A1*28 variants is available at the National Cancer Centre, Tel: (6436-8320), and test results will be returned within 48 hours.

The era of genomics is producing an abundance of information about genetic variation within and across populations. As studies gradually dissect the information and establish linkages between genetic variations and response to drugs, they add to a body of knowledge that will help physicians tailor therapies for the individual characteristics of their patients. 

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References

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10. www.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience

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18. Neonatology 2009, 96:150-155

19. Singapore Genome Variation Project, http://www.statgen.nus.edu.sg/~SGVP/