Lecture 18: Pharmacogenomics Flashcards

Question

Genetic Variability Influences Drug Metabolism Enzymes

Answer 1

*75% of all drugs are metabolized by 'CYP3A4 + CYP2D6' *2D6 contributes~20% of all drugs, although it is only 1.5% of total liver content diagram on slide 24

Answer 2

CYP 2D6 in Caucasians: – PM: 7% High plasma drug level, toxicity – IM: 40% Lower dose in some patients – EM: 50% Normal metabolizers STD dose – UM: 3% Very low drug level, higher dose CYP 2C19 in Caucasians: – PM: 3% – IM: 27% – EM: 70% Normal metabolizers

Answer 3

1 * The dose determines both efficacy and safety of a drug. Genetic factors play a role. 2 * An example is warfarin: * SNPs in CYP2C9 (enzyme metabolizing warfarin) & VKORC1 (enzyme inhibited by warfarin) determine the dose requirement. Loss-of-function SNPs in either or both genes cause reduced enzyme activity and lower warfarin doses is required, to avoid overexposure, and achieve therapeutic anticoagulation. 3 * Other examples are with anticancer drugs: 4 * TPMT and NUDT15 SNPs and thiopurines, 5 * DPYD polymorphisms and fluoropyrimidines, and 6 * UGT1A1 polymorphisms and irinotecan. 6 * In these cases, a SNP either reduces or abolishes the activity of the relevant enzyme resulting in reduced metabolism of the anticancer drug, overexposure and dose-dependent toxicity, causing bone marrow suppression and/or severe diarrhoea.

Answer 4

Genetic SNPs in cytochrome P450 enzymes CYP2D6, CYP2C19 and CYP2C9, thiopurine Smethyltransferase (TPMT), and N-acetyltransferase type 2 (NAT2). UM: ultra-rapid metabolizer; RA: rapid acetylator; EM: extensive metabolizer; IA: intermediate acetylator; IM: intermediate metabolizer; SA: slow acetylator; PM: poor metabolizer; AUC: area under the curve;

Answer 5

1 * Some diseases are due to specific mutations in a gene. 2. Can be many other mutations that have different effects. 3 * The protein may not work correctly, or not be made at all. 4 * Drugs can be created based on how the mutation affects the protein. The drug only works for the specific mutation, eg 'Cystic Fibrosis' 5 * Ivacaftor, trialled in the 4% of patients carrying G551D mutation, led to a 55% reduction in the pulmonary exacerbation rate. 6 * Combination of elexacaftor, tezacaftor and ivacaftor, used in patients with at least one copy of Phe508del, reduced the exacerbation rate by 63%. * CVD 7 * Gain-of-function mutations in the PCSK9 gene lead to high LDL-C levels and premature CVD & vise versa. 8 * Anti-PCSK-9 antibodies, reduce LDL-C by 54% when given fortnightly and CVD events.

Answer 6

CODEINE AND NORTRIPTYLINE TABLE/DIAGRAM ON SLIDE 30

Answer 7

DIAGRAM ON SLIDE 31

Answer 8

1 * Warfarin is the most common oral anticoagulant in the world 2 * Therapeutic range: INR 2-3 (2.5-3.5 for prosthetic heart valves) 3 * INR <2: risk of thromboembolic event 4 * INR >3: risk of bleeding complications 5 * 30 to 35% of the variability in warfarin response is due to genetic variants, which is more than clinical variables alone.

Answer 9

1 * Metabolism of warfarin is dependent on CYP2C9 and CYP2C9 LOF alleles (CYP2C9*2 and CYP2C9*3) have been associated with over-anticoagulation and an increased risk of bleeds. 2 * Pharmacogenetic algorithm; age, sex, weight, height, self-declared race, use of amiodarone, use of enzyme inducers, VKORC1 genotypes, and predicted phenotypes according to CYP2C9 polymorphisms 3 * Three recent RTCs have produces conflicting results. Possibly due to different populations groups. 4 * Warfarin use has dropped over the last 10 years from 77 to 12% in specific indications like atrial fibrillation.

Answer 10

1 * Presented with 2 weeks of extensive bruising & back pain. 2 * Pale, tachycardic, no fever, ↓ Hb, ↑ WCC, ↓ platelets 3 * Blood film → ↑ lymphocytes → acute lymphocytic leukaemia, (bone marrow) 4 * Responded well to chemotherapy 5 * Maintenance dose of 6-mercaptopurine & MTX 6 * Prior to treatment blood taken for TPMT – level OK 7 * Severe neutropenic sepsis – treated with antibiotics 8 * Had a blood transfusion for anaemia – gave false TPMT level 9 * TPMT genotype – homozygous for TPMT*3A 10 * Reduced dose of 6MP and remained disease free

Answer 11

FLOWCHART SLIDE 35

Answer 12

DIAGRAM TO GRAPH ..SLIDE 36

Answer 13

DIAGRAM/GRAPH ON SLIDE 37

Answer 14

1. Tamoxifen known as the most important adjuvant endocrine treatment in patients with estrogen receptor (ER) positive breast cancer. 2. It inhibits tumor growth and promotes apoptosis in ER-positive tumors, resulting in a reduced risk of recurrence and death from breast cancer.

Answer 15

1. Between 2018 and 2021, 2 studies showed a relation between CYP2D6 genotype and breast cancer recurrence as well as breast cancer-specific mortality after tamoxifen treatment. 2 * Four studies reported no association with clinical outcome in tamoxifen treatment. 3 * The controversy regarding the association of CYP2D6 genotype and tamoxifen- related clinical outcome continues. 4 * This controversy will exist until large RCTs are performed.

Answer 16

1. * ADRs can be divided into Type A and Type B reactions, both can be affected by genetic factors. 2. * A great deal of progress has been made in identifying genetic predisposing factors for ADRs over the past 20 years. 3. * Type A, ADRs are an augmentation of the pharmacological actions of a drug and show typical dose dependency, with a reduction in dose leading to improvement in ADRs. 4. * The examples given in the previous slides on dose are illustrations of Type A ADRs.

Answer 17

1 * Type B ADRs cannot be easily explained based on the pharmacology of the drug, 2 * There is no clear dose dependency and drug discontinuation stops the ADR. 3 * Many of these ADRs are immune mediated. 4 * HLA alleles predispose to these reactions. 5 * Such as associations with flucloxacillin hepatitis and carbamazepine hypersensitivity.

Answer 18

1. Implementation of pharmacogenomics into clinical practice has been slow, and pharmacogenomic testing has been restricted to certain specialist centres. 2 * Due to a perceived lack of clinical evidence, inability to access genotyping tests, lack of clarity on costeffectiveness, lack of knowledge on how to interpret pharmacogenomic tests and the actions to take when a patient has a variant allele, education, funding, worries about disruption to the normal clinical pathways and concerns over confidentiality issues. 3 * Evidence needed on polypharmacy (≥5 concomitant drugs) and multimorbidity in the elderly.

Answer 19

1. Genomic studies are highly Eurocentric and to lack ethnic diversity ...2. exacerbates already-existing health in equalities. 3. 97% of GWAS data participants are of European ancestry with only 2.2% Asian, 0.02% African. 4. Lack of diversity is a problem in pharmacogenomic studies eg ....5. * Most warfarin dosing algorithms have been based on CYP2C9*2 and CYP2C9*3 SNPs, which are prevalent in European populations but largely absent in African-ancestry populations. Studies that have evaluated the role of CYP2C9 SNPs that are more prevalent in African populations are scant. 6. Lack of consideration of ethnic diversity is also seen in drug labels.

Answer 20

1. In oncology, MPS has identified driver mutations in somatic cancer genomes. Leading to the development of drugs that target these mutations. 2. * Eg Vemurafenib, inhibits BRAF and crizotinib, inhibits ALK. 3. * Most successful drug classes developed are tyrosine kinase inhibitors, eg imatinib, which targets the BCR–ABL1 fusion gene in CML. Transforming prognosis of CML be similar to age matched individuals. 4. * This is not the case with most solid tumours. Initially there is a dramatic response that relapses due to the development of new mutations. 5. * The challenge - identify best combination of therapies targeting the aberrant pathway(s) to lead to increased overall survival.

Answer 21

1 * Genetic variation contributes to inter-individual differences in drug response 2 * Through personalized or precision medicine, pharmacogenomics is expected to give: 3 * Better, safer drugs the first time 4 * More accurate methods of determining appropriate drug dosages 5 * Implementation into clinical practice has been slow. 6 * Genomics data will help in the early stages of drug development, identifying hazards that might not be detectable otherwise. 7 * Multimodal algorithms using clinical (eg, age, sex & BMI) + genetic factors, and other -omic biomarkers, are needed. 8 * HOWEVER, MANY CASES ARE NOT YET READY FOR PRIME TIME!!! But with research, pharmacogenomics will lead to improved human health.