Poster Presentation Australian Society for Medical Research Annual Scientific Meeting 2016

Clinically Actionable Pharmacogenotypes of CYP2C9 Relevant to Gastrointestinal Bleeding of Celecoxib in Community-Dwelling Older Australians (#127)

Thilani H. Dias 1 , Nilofar Daneshi 1 , Mohitosh Biswas 1 , Elizabeth Holliday 2 3 , Irene Munro 1 , Karen Kerr 1 , John Attia 2 3 , Rodney Scott 1 4 , Liz Milward 1
  1. School of Biomedical Sciences and Pharmacy,Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, 2308, Australia
  2. Clinical Research Design, IT and Statistical Support (CReDITSS) Unit, Hunter Medical Research Institute, Newcastle, NSW, 2305, Australia
  3. Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Faculty of Health and Medicine, The University of Newcastle, Newcastle, NSW 2305, Australia
  4. Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW,2305, Australia

Introduction
The non-steroidal anti-inflammatory drug celecoxib is metabolized by CYP2C91. Certain gene variants causing poor or intermediate CYP2C9 activity may increase risks of gastrointestinal (GI) bleeding with celecoxib and are therefore clinically actionable i.e. justify change of dose or use of another drug2. Risks of GI bleeding may be further increased by co-prescription of various other drugs.

Objectives
To assess the prevalence of clinically actionable CYP2C9 genotypes and celecoxib use in older community-dwelling Australians and the prevalence of potential multifactorial drug-gene interactions involving co-prescription of drugs associated with GI bleeding.

Methods
Clinically actionable gene variants were identified from the Pharmacogenomics Knowledge Base, Clinical Pharmacogenetics Implementation Consortium and US Food and Drug Administration (FDA)2,3. Genotype data were obtained for 2121 community-dwelling older Australians aged 55 years and above from the Hunter Cohort Study using Affymetrix Kaiser Axiom arrays or imputed from 1000 Genomes and Hap Map Phase II European panels4.

Results
Of the 2121 participants with genotype data, 250 (12%) had intermediate and 18 (~1%) had poor metabolising CYP2C9 genotypes i.e. almost 13% had at least one clinically actionable genotype increasing GI bleeding risk. Prevalence of celecoxib use in these two groups was 4.4% and 5.6% respectively. This represented 15% of the 79 participants on celecoxib for whom genotype data were available. Of the 137 participants on celecoxib, nearly half (56; 41%) were co-prescribed other drugs that may increase GI bleeding. Of the 38 participants on other drugs with genotype data available, 8 (21%) also had the intermediate metabolising genotype.

Conclusion
The results suggest that considerable numbers of people using the non-steroidal anti-inflammatory drug celecoxib are at risk of simple or multifactorial drug-gene interactions related to GI bleeding. There may be strong potential for prescribers to improve celecoxib safety by taking genotype and medication reviewing into account.

 

 

  1. 1.Gong, L., et al., Celecoxib pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics and Genomics, 2012. 22(4): p. 310-318. 2.The pharmacogenomics knowledgebase (PharmGKB) 2016, accessed 10 April 2016, https://www.pharmgkb.org/index.jsp 3.The pharmacogenomics knowledgebase (PharmGKB).Clinical pharmacogenetics implementation consortium (CPIC) 2016, accessed 10 April 2016, https://www.pharmgkb.org/page/cpic 4.McEvoy, M., et al., Cohort Profile: The Hunter Community Study. International Journal of Epidemiology, 2010. 39(6): p. 1452-1463