DOI: 10.5176/2345-783X_PHARMA17.35
Authors: Thilani H. Dias, Mohitosh Biswas ,Nilofar Daneshi, Elizabeth Holliday, Stephen Hancock, Irene Munro1, Karen Kerr1, John Attia, Rodney J. Scott, and Elizabeth A. Milward
Abstract:
Methotrexate is a commonly used immunomodulating drug for the treatment of cancer and autoimmune disorders. There is heterogeneity in patient responses to methotrexate ranging from therapeutic failure to drug toxicities. Accumulating evidence suggests that this may partly reflect drug-drug or druggene interactions that alter safety or efficacy of methotrexate. However there is a paucity of studies investigating the prevalence of potential multifactorial drug-gene interactions involving cumulative effects of DDI and DGI. The purpose of our study is to investigate the prevalence of potential drug-drug or drug-gene interactions and multifactorial drug-gene interactions relevant to methotrexate among community dwelling older Australians aged 55 years or above. Medication data were self-reported and genotype data were obtained from Affymetrix Kaiser Axiom array analysis combined with imputation from 1000 Genome or HapMap Phase II European reference panels. Of the participants who were on methotrexate, 74{6e6090cdd558c53a8bc18225ef4499fead9160abd3419ad4f137e902b483c465} had at least one potential DDI. For these participants, the most common types of potential DDIs were between methotrexate and NSAIDs, which are categorized as severe, with 79{6e6090cdd558c53a8bc18225ef4499fead9160abd3419ad4f137e902b483c465} of these participants at risk of one or more such interactions. In addition, all the participants exposed to methotrexate and having genotype data had either rs4673993 of the 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase /IMP cyclohydrolase (ATIC) gene either alone or both rs1801133 of the methylenetetrahydrofolate reductase (MTHFR) gene or rs4673993 of ATIC gene, predicted to be associated with methotrexate toxicity and efficacy. Overall, the prevalence of multifactorial DGI was 79{6e6090cdd558c53a8bc18225ef4499fead9160abd3419ad4f137e902b483c465} therefore many of the participants taking methotrexate who had the above gene variants were also found to be at risk of having one or more relevant severe or moderate drug-drug interactions. In conclusion, our findings highlight that increased awareness and consideration of the combined effects of both drug-drug and drug-gene interactions are important to enhance therapeutic outcomes for patients taking methotrexate.
Keywords: Pharmacogenomics, drug-drug interactions, drug-gene interactions, methotrexate, community
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