Podcast
Questions and Answers
What percentage of hospital admissions related to drug toxicity occurred in the study mentioned?
What percentage of hospital admissions related to drug toxicity occurred in the study mentioned?
Which drug is not mentioned as having common adverse drug reactions in the study?
Which drug is not mentioned as having common adverse drug reactions in the study?
What is the primary focus of pharmacogenetics?
What is the primary focus of pharmacogenetics?
What was the reported annual cost of drug toxicity-related admissions to the NHS?
What was the reported annual cost of drug toxicity-related admissions to the NHS?
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Which genetic variant is directly associated with prolonged apnea after succinylcholine administration?
Which genetic variant is directly associated with prolonged apnea after succinylcholine administration?
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What is the most common adverse reaction identified in the study?
What is the most common adverse reaction identified in the study?
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Which of the following drugs is specifically highlighted for its a pharmacogenetic association that has not translated into clinical practice?
Which of the following drugs is specifically highlighted for its a pharmacogenetic association that has not translated into clinical practice?
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What aspect is essential for determining a good pharmacogenetic test?
What aspect is essential for determining a good pharmacogenetic test?
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What is the primary role of TPMT testing in azathioprine therapy?
What is the primary role of TPMT testing in azathioprine therapy?
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In which ethnicities are NUDT15 variants considered more important in pharmacogenetic testing?
In which ethnicities are NUDT15 variants considered more important in pharmacogenetic testing?
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What percentage of patients receiving fluoropyrimidines will likely develop severe toxicity (CTCAE grade ≥3)?
What percentage of patients receiving fluoropyrimidines will likely develop severe toxicity (CTCAE grade ≥3)?
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What is the potential impact of severe toxicity from fluoropyrimidine drugs on patient treatment?
What is the potential impact of severe toxicity from fluoropyrimidine drugs on patient treatment?
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Which of the following adverse effects is most commonly associated with 5-Fluorouracil treatment?
Which of the following adverse effects is most commonly associated with 5-Fluorouracil treatment?
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What is a significant financial consequence of the grade 3-4 toxicity related to 5-Fluorouracil treatment?
What is a significant financial consequence of the grade 3-4 toxicity related to 5-Fluorouracil treatment?
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Which pharmacogenetic marker plays a smaller role compared to NUDT15 in the context of drug metabolism?
Which pharmacogenetic marker plays a smaller role compared to NUDT15 in the context of drug metabolism?
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What is the hospitalization duration for patients experiencing diarrhea due to fluoropyrimidine treatment?
What is the hospitalization duration for patients experiencing diarrhea due to fluoropyrimidine treatment?
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What is the primary consequence of complete DPD deficiency when treated with 5FU?
What is the primary consequence of complete DPD deficiency when treated with 5FU?
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Which of the following statements about partial DPD deficiency is true?
Which of the following statements about partial DPD deficiency is true?
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Why is there no effective DPD enzyme assay for screening?
Why is there no effective DPD enzyme assay for screening?
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What is the frequency of the 'common' DPYD IVS14+1G>A splice junction variant in the population?
What is the frequency of the 'common' DPYD IVS14+1G>A splice junction variant in the population?
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What has the FDA warned regarding 5FU and capecitabine?
What has the FDA warned regarding 5FU and capecitabine?
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How is DPD deficiency categorized in individuals?
How is DPD deficiency categorized in individuals?
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Which of the following is an accurate descriptor of 5FU metabolism?
Which of the following is an accurate descriptor of 5FU metabolism?
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What is a major challenge in predicting toxicity from DPD deficiency?
What is a major challenge in predicting toxicity from DPD deficiency?
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What is the recommended dosing strategy for a patient with a zero TPMT phenotype?
What is the recommended dosing strategy for a patient with a zero TPMT phenotype?
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What does a normal TPMT phenotype indicate for dosing of azathioprine (AZA)?
What does a normal TPMT phenotype indicate for dosing of azathioprine (AZA)?
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In the prospective study mentioned, what was the percentage of patients who experienced AZA withdrawal in the group with high TPMT activity?
In the prospective study mentioned, what was the percentage of patients who experienced AZA withdrawal in the group with high TPMT activity?
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What was a significant finding regarding neutropenia in patients treated with azathioprine?
What was a significant finding regarding neutropenia in patients treated with azathioprine?
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What is the significance of p=0.002 in the study involving IBD patients with AZA withdrawal?
What is the significance of p=0.002 in the study involving IBD patients with AZA withdrawal?
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For a patient with intermediate TPMT activity, what is the recommended approach to dosing?
For a patient with intermediate TPMT activity, what is the recommended approach to dosing?
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What was the health outcome for the 48-year-old male patient who had a TPMT phenotype of zero and was treated with azathioprine?
What was the health outcome for the 48-year-old male patient who had a TPMT phenotype of zero and was treated with azathioprine?
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In patients treated with azathioprine, what is a potential side effect that is not explained by TPMT deficiency?
In patients treated with azathioprine, what is a potential side effect that is not explained by TPMT deficiency?
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Which DPYD variant is associated with a high odds ratio for toxicity according to the meta-analysis?
Which DPYD variant is associated with a high odds ratio for toxicity according to the meta-analysis?
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What is the percentage of the standard dose recommended for the variant c.1236G>A/HapB3 c.1129-5923C>G?
What is the percentage of the standard dose recommended for the variant c.1236G>A/HapB3 c.1129-5923C>G?
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Which of the following statements regarding the effect of compound heterozygous genotypes is true?
Which of the following statements regarding the effect of compound heterozygous genotypes is true?
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Which organization recommended testing for four specific DPYD variants prior to therapy?
Which organization recommended testing for four specific DPYD variants prior to therapy?
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How prevalent are the four DPYD variants that predict toxicity in the population?
How prevalent are the four DPYD variants that predict toxicity in the population?
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Which term best describes the likelihood of experiencing Grade 3-4 toxicity in patients with certain DPYD variants?
Which term best describes the likelihood of experiencing Grade 3-4 toxicity in patients with certain DPYD variants?
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Which DPYD variant has the highest odds ratio for toxicity, based on the provided studies?
Which DPYD variant has the highest odds ratio for toxicity, based on the provided studies?
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What is a primary benefit of testing for DPYD variants in cancer therapy?
What is a primary benefit of testing for DPYD variants in cancer therapy?
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Study Notes
Overview of Pharmacogenetics
- Pharmacogenetics studies how genetic variation affects individual responses to drugs.
- First used the term in 1959, emphasizes genetic influence on drug metabolism.
- Butyrylcholinesterase (BCHE) gene variation can cause severe reactions to succinylcholine, a muscle relaxant.
Adverse Drug Reactions (ADRs)
- 6.5% of hospital admissions attributed to drug toxicity, with an annual cost of £466 million to the NHS.
- Gastrointestinal bleeding is the most common ADR among patients using drugs like aspirin and warfarin.
- Median hospital stay for ADRs is eight days, contributing to healthcare system burden.
Key Pharmacogenetic Associations
- Thiopurine and fluoropyrimidine drugs demonstrate clinically useful pharmacogenetic applications.
- TPMT (thiopurine methyltransferase) testing can guide azathioprine dosing to avoid toxicity.
- NUDT15 variants are significant in Asian patients, indicating the need for broad genetic screening.
Azathioprine (AZA) and TPMT Testing
- TPMT phenotyping categorizes patients into high, intermediate, and normal activity levels.
- Dosage recommendations vary based on TPMT levels, aiming to minimize the risk of severe side effects like neutropenia.
- Case studies highlight importance of testing; wrong dosing can lead to fatal outcomes.
Fluoropyrimidines – 5-Fluorouracil (5FU)
- 5FU is a first-line treatment for solid tumors, yet 10-20% of patients face severe toxicity.
- Adverse effects lead to treatment interruptions and significant healthcare costs tied to hospitalization.
Dihydropyrimidine Dehydrogenase (DPD) Deficiency
- DPD deficiency linked to 5FU toxicity, with partial deficiency affecting about 4-6% of the population.
- Immunoassays for DPD activity face practical limitations; genetic testing is often required for accurate identification.
Genetic Variants and Toxicity Prediction
- Several DPYD variants correlate with severe toxicity risk associated with 5FU treatment.
- Testing for these variants can reduce the incidence of severe ADRs and is deemed cost-effective.
- Guidelines have shifted to recommend genetic testing prior to fluropyrimidine therapy.
Clinical Practice Changes
- Recent guidelines from EMA and NHSE endorse pre-treatment testing for four specific DPYD variants.
- Testing improves patient safety and efficacy of treatments, demonstrating the value of pharmacogenetic approaches in clinical settings.
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