Drug Safety

, Volume 34, Issue 12, pp 1167–1175 | Cite as

Pharmacogenetic Risk for Adverse Reactions to Irinotecan in the Major Ethnic Populations of Singapore

Regulatory Evaluation by the Health Sciences Authority
  • Cynthia Sung
  • Pui Ling Lee
  • Liesbet L. Tan
  • Dorothy S.L. Toh
Short Communication


Background: For genetic polymorphisms known to alter drug effect or safety, regulatory authorities can tap into population genomic databases and other sources of allele and genotype distribution data to make a more informed decision about the anticipated impact of such variants on the main ethnic groups in a country’s population.

Objective: The aim of this short communication is to describe how the Singapore Health Sciences Authority (HSA) made use of allele and genotype distributions in the main ethnic groups in Singapore (Chinese, Malay, Indian) and population genetic tools to compare with North American Caucasians and Japanese.

Methods: Published papers and publicly accessible genomic databases were searched up to August 2009 to obtain allele and genotype frequencies for UGT1A1*6 and *28, two common variants of UGT1A1, a gene that encodes for a key enzyme in the pathway of irinotecan metabolism. These variants are associated with greater risk of serious toxicity.

Results: In Singapore, the combined prevalence of three high-risk genotypes, UGT1A1*6/*6, *6/*28 and *28/*28, is 9.7% in Chinese, 5.0% in Malays and 18.7% in Indians, compared with 11.5% in North American Caucasians and 8.1% in Japanese. Indians are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*28 compared with Chinese and Japanese, and at an even higher risk compared with North American Caucasians. On the other hand, Chinese and Japanese are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*6 relative to Indians in Singapore or North American Caucasians. Population genotype data were the basis for the HSA to request revision of the package insert from manufacturers of irinotecan products. Moreover, the data provided the impetus for the HSA to publicize the availability of UGT1A1 genetic testing at the National Cancer Centre.

Conclusion: With the growing volume of genomic data and pharmacogenomic associations, a regulatory authority is now able to more readily utilize population genetic information and tools to supplement evaluations of drug products pertinent to the country’s ethnic demography.



We are grateful to Associate Professors Balram Chowbay and Lee Soo Chin for input on their experience with the useof irinotecan in local clinical practice. We also wish to express our appreciation to members of the HSA Pharmaco-genetics Advisory Committee for their guidance, and to Dr John Lim, CEO of the HSA, Dr Christina Lim, GroupDirector, Health Products Regulation Group, HSA, and Cheng Leng Chan, Division Director of Vigilance, Compliance and Enforcement, HSA, for encouraging us to apply genomic information for improvement of the regulatory functions at the HSA.

No external sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this study.


  1. 1.
    Department of Statistics Singapore [online]. Available from URL: www.singstat.gov.sg [Accessed 2011 Oct 10]
  2. 2.
    Cohen DP, Adams DJ, Flowers JL, et al. Pre-clinical evaluation of SN-38 and novel camptothecin analogs against human chronic B-cell lymphocytic leukemia lymphocytes. Leuk Res 1999 Nov 1; 23(11): 1061–70PubMedCrossRefGoogle Scholar
  3. 3.
    Pharmagenomics Knowledge Base [online]. Available from URL: www.pharmgkb.org [Accessed 2011 Jun 7]
  4. 4.
    Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyl-transferase 1 in Gilbert’s syndrome. N Engl J Med 1995 Nov 2; 333(18): 1171–5PubMedCrossRefGoogle Scholar
  5. 5.
    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 Apr 15; 22(8): 1382–8PubMedCrossRefGoogle Scholar
  6. 6.
    Jada SR, Lim R, Wong CI, et al. Role of UGT1A1*6, UGT1A1*28 and ABCG2 c.421C>A polymorphisms in irinotecan-induced neutropenia in Asian cancer patients. Cancer Sci 2007 Sep 1; 98(9): 1461–7PubMedCrossRefGoogle Scholar
  7. 7.
    Carlini LE, Meropol NJ, Bever J, et al. UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/ irinotecan. Clin Cancer Res 2005 Feb 1; 11(3): 1226–36PubMedGoogle Scholar
  8. 8.
    Han J-Y, Lim H-S, Shin ES, et al. Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 2006 May 20; 24(15): 2237–44PubMedCrossRefGoogle Scholar
  9. 9.
    Xiang X, Jada SR, Li HH, et al. Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients. Pharmacogenet Genomics 2006 Sep; 16(9): 683–91PubMedCrossRefGoogle Scholar
  10. 10.
    Sandanaraj E, Jada SR, Shu X, et al. Influence of UGT1A9 intronic I399C>T polymorphism on SN-38 glucuronidation in Asian cancer patients. Pharmacogenomics J 2008 Jun; 8(3): 174–85PubMedCrossRefGoogle Scholar
  11. 11.
    Cecchin E, Innocenti F, D’Andrea M, et al. Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol 2009 May 20; 27(15): 2457–65PubMedCrossRefGoogle Scholar
  12. 12.
    Innocenti F, Kroetz DL, Schuetz E, et al. Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. J Clin Oncol 2009 Jun 1; 27(16): 2604–14PubMedCrossRefGoogle Scholar
  13. 13.
    van der Bol JM, Mathijssen RHJ, Creemers G-JM, et al. A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan. Clin Cancer Res 2010 Jan 15; 16(2): 736–42PubMedCrossRefGoogle Scholar
  14. 14.
    Marcuello E, Altés A, Menoyo A, et al. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 2004 Aug 16; 91(4): 678–82PubMedGoogle Scholar
  15. 15.
    Rouits E, Boisdron-Celle M, Dumont A, et al. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res 2004 Aug 1; 10(15): 5151–9PubMedCrossRefGoogle Scholar
  16. 16.
    Araki K, Fujita K-I, Ando Y, et al. Pharmacogenetic impact of polymorphisms in the coding region of the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with cancer. Cancer Sci 2006 Nov 1; 97(11): 1255–9PubMedCrossRefGoogle Scholar
  17. 17.
    Massacesi C, Terrazzino S, Marcucci F, et al. Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer 2006 Mar 1; 106(5): 1007–16PubMedCrossRefGoogle Scholar
  18. 18.
    Kweekel DM, Gelderblom H, Van der Straaten T, et al. UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study. Br J Cancer 2008 Jul 22; 99(2): 275–82PubMedCrossRefGoogle Scholar
  19. 19.
    Liu C-Y, Chen P-M, Chiou T-J, et al. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer 2008 May 1; 112(9): 1932–40PubMedCrossRefGoogle Scholar
  20. 20.
    Ruzzo A, Graziano F, Loupakis F, et al. Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Pharmacogenomics J 2008 Aug 1; 8(4): 278–88PubMedCrossRefGoogle Scholar
  21. 21.
    US FDA. Advisory Committee for Pharmaceutical Science, Clinical Pharmacology Subcommittee. November 3–4, 2004 [online]. Available from URL: www.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience [Accessed 2009 Sep 1]
  22. 22.
    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 Jan 1; 47(1): 78–86PubMedCrossRefGoogle Scholar
  23. 23.
    Hoskins JM, Goldberg RM, Qu P, et al. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst 2007 Sep 5; 99(17): 1290–5PubMedCrossRefGoogle Scholar
  24. 24.
    Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can UGT1A1 geno-typing reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med 2009 Jan 1; 11(1): 15–20CrossRefGoogle Scholar
  25. 25.
    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 Jul 1; 17(7): 497–504PubMedCrossRefGoogle Scholar
  26. 26.
    Onoue M, Terada T, Kobayashi M, et al. UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients. Int J Clin Oncol 2009 Apr 24; 14(2): 136–42PubMedCrossRefGoogle Scholar
  27. 27.
    Pharmaceuticals and medical devices safety information: irinotecan hydrochloride [online]. Available from URL: www.pmda.go.jp/english/service/pdf/precautions/PMDSI-248.pdf [Accessed 2009 Aug 6]
  28. 28.
    Zhou YY, Lee LY, Ng SY, et al. UGT1A1 haplotype mutation among Asians in Singapore. Neonatology 2009 Jan 1; 96(3): 150–5PubMedCrossRefGoogle Scholar
  29. 29.
    National University of Singapore. Singapore Genome Variation Project [online]. Available from URL: www.nus-cme.org.sg/SGVP [Accessed 2011 Jun 7]
  30. 30.
    International HapMap Project [online]. Available from URL: http://www.hapmap.org [Accessed 2011 Jun 7]
  31. 31.
    Ando Y, Chida M, Nakayama K, et al. The UGT1A1*28 allele is relatively rare in a Japanese population. Pharmacogenetics 1998 Aug 1; 8(4): 357–60PubMedCrossRefGoogle Scholar
  32. 32.
    Beutler E, Gelbart T, Demina A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 1998 Jul 7; 95(14): 8170–4PubMedCrossRefGoogle Scholar
  33. 33.
    Chen J, Teo YY, Toh DSL, et al. Interethnic comparisons of important pharmacology genes using SNP databases: potential application to drug regulatory assessments. Pharmacogenomics 2010 Aug 1; 11(8): 1077–94PubMedCrossRefGoogle Scholar
  34. 34.
    Wright S. Variability within and among natural populations. Chicago (IL): University of Chicago, 1978Google Scholar
  35. 35.
    Teo YY, Small KS. A novel method for haplotype clustering and visualization. Genet Epidemiol 2010 Jan; 34(1): 34–41PubMedGoogle Scholar
  36. 36.
    Health Sciences Authority [online]. Available from URL: www.hsa.gov.sg [Accessed 2011 Oct 10]
  37. 37.
    Health Sciences Authority. Association between UGT1A1 variant alleles and irinotecan-induced severe neutropenia. Adverse Drug Reaction News Bulletin 2010; 12 (1) [online]. Available from URL: http://www.hsa.gov.sg/publish/hsaportal/en/health_products_regulation/safety_information/adr_bulletin.html [Accessed 2010 Apr 10]
  38. 38.
    Teo YY, Sim X, Ong RT, et al. Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations. Genome Res 2009 Nov; 19(11): 2154–62PubMedCrossRefGoogle Scholar
  39. 39.
    Sunakawa Y, Ichikawa W, Fujita K-I, et al. UGT1 A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer Chemother Pharmacol 2011 Aug; 68(2): 279–84PubMedCrossRefGoogle Scholar
  40. 40.
    Hu Z-Y, Yu Q, Zhao Y-S. Dose-dependent association between UGT1A1*28 polymorphism and irinotecan-induced diarrhoea: a meta-analysis. Eur J Cancer 2010 Jul 1; 46(10): 1856–65PubMedCrossRefGoogle Scholar
  41. 41.
    Hu Z-Y, Yu Q, Pei Q, et al. Dose-dependent association between UGT1A1*28 genotype and irinotecan-induced neutropenia: low doses also increase risk. Clin Cancer Res 2010 Aug 1; 16(15): 3832–42PubMedCrossRefGoogle Scholar
  42. 42.
    Palomaki GE, Bradley LA, Douglas MP, et al. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med 2009 Jan 1; 11(1): 21–34PubMedCrossRefGoogle Scholar
  43. 43.
    Ishida H, Fujita K-I, Akiyama Y, et al. Regimen selection for first-line FOLFIRI and FOLFOX based on UGT1A1 genotype and physical background is feasible in Japanese patients with advanced colorectal cancer. Jpn J Clin Oncol 2011 May; 41(5): 617–23PubMedCrossRefGoogle Scholar
  44. 44.
    Gold HT, Hall MJ, Blinder V, et al. Cost effectiveness of pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 before irinotecan administration for metastatic colorectal cancer. Cancer 2009 Sep 1; 115(17): 3858–67PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2011

Authors and Affiliations

  • Cynthia Sung
    • 1
  • Pui Ling Lee
    • 1
  • Liesbet L. Tan
    • 1
  • Dorothy S.L. Toh
    • 1
  1. 1.Health Products Regulation GroupHealth Sciences AuthoritySingapore

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