Pharmacogenetics in the clinic Flashcards
What factors contribute to variable inter-individual drug response?
- Demographic
- Environment
- Co-morbidities
- Drug-drug interactions
- Genomic variation
What percentage of patients benefit from drug therapy?
30-60%
What is the percentage of adverse drug reactions (ADRs) that lead to hospitalization?
6.5%
What is pharmacogenomics?
Study and response of the genetic determinants of drug response
What percentage of phase-dependent metabolism of clinically used drugs is mediated by CYP families 1-3?
70-80%
What was the first P450 enzyme purified to homogeneity?
CYP2B4
What do polymorphic forms of P450s lead to?
Development of significant number of adverse drug reactions (ADRs)
What is the cost implication of treating patients with polymorphic forms of P450s?
Higher than those with non-polymorphic alleles
What percentage of subjects are non-responders to drug therapy?
Around 30-60%
What is the role of the 10,000 Genomes project?
Sequencing the whole genome of families with rare diseases and patients with common sequences
What does CPIC stand for?
Clinical Pharmacogenomics Implementation Consortium
What proportion of the population carries at least 1 actionable pharmacogenetic variant?
98.5% of Whites and 99.1% of African-Americans in the US
What is the function of CYP2C19 in relation to clopidogrel?
Prodrug requiring activation by CYP2C19
What is the effect of the 11 genotype on platelet aggregation when treated with clopidogrel?
Reduction in platelet aggregation
What are the genotypes of a CYP2C19 poor metaboliser?
2/2
3/3
2/3
What is the therapeutic outcome for a CYP2C19 poor metaboliser?
Avoid clopidogrel if possible; use prasugrel or ticagrelor
List the options for statins.
- Atorvastatin
- Fluvastatin
- Lovastatin
- Pitavastatin
- Pravastatin
- Rosuvastatin
- Simvastatin
What role does SLOC1B1 play in the metabolism of statins?
Facilitates the hepatic uptake of statins
What is the association of the ABCG2 variant p.Q141K with rosuvastatin?
Associated with 30-40% reduced protein expression and increased plasma levels of rosuvastatin
What are the two most extensively studied variants of CYP2C9?
- CYP2C9*2 (p.R114C)
- CYP2C9*3 (p.I359L)
What is statin induced myopathy?
Ranges from mild myalgia to very rare but life-threatening rhabdomyolysis
What does the SLOC1B1*5 variant indicate?
Higher plasma levels cause muscle toxicity
What is the significance of diplotypes in pharmacogenomics?
Haplotype pairs on homologous chromosomes
What treatment adjustments are needed for SLOC1B1 decreased function?
Treatment varies based on SAMS risk; high, moderate, or low intensity statins
What is familial hypercholesterolemia?
Functional mutation in LDLR, APOB, or PCSK9 gene leading to premature coronary artery disease
What should be considered for anticoagulation if warfarin is used?
Pharmacogenetic considerations related to CYP2C9
What are the typical substrates of CYP2C9?
- Warfarin
- Fluvastatin
- Tolbutamide
- NSAIDs
- Phenytoin
What is the range of clinical therapeutic doses for warfarin?
0.5 to 20 mg/day
What is the difference between R-warfarin and S-warfarin?
S-warfarin is more biologically active and potent than R-warfarin
What is the impact of CYP2C9*3 on warfarin dosing?
Increases risk of warfarin-induced bleeding
What should be done for a patient with a homozygous *2 allele in CYP2C19?
Expect poorer outcomes when treated with clopidogrel
What is the recommendation for a patient with high SAMS risk and SLOC1B1 decreased function?
Treat with 80 mg of Atorvastatin
What is the importance of monitoring in familial hypercholesterolemia?
Initiation of early lipid lowering treatment and monitoring in specialist metabolic clinic
What percentage of healthy and random controls express the homozygous wild-type CYP2C9 genotype?
60-62%
What percentage of patients expressed the CYP2C9 homozygous wild-type genotype when given a low dose of warfarin?
20%
By what percentage was the heterozygous CYP2C9 genotype reduced compared to the homozygous wild type?
35-36%
What is the percentage increase of patients with at least one defective allele of CYP2C9 when given a low dose of warfarin?
60%
What percentage of healthy and random volunteers did not express the CYP2C9 homozygous mutant alleles?
5-6%
What is the warfarin dose requirement for homozygous 2/2 and 3/3 genotypes of CYP2C9?
~3mg for *2 and ~1mg for *3
What is the mean warfarin dose tolerated by individuals with wild-type CYP2C9?
~5mg
What is the association between the presence of one or more variant CYP2C9 alleles and warfarin dose requirement?
Low (<1.5 mg) dose requirement
What factors are associated with having a low dose requirement for warfarin?
- Increased risk of problems during induction period
- Increased risk of major bleeding episodes following induction
List additional factors affecting warfarin dose requirement.
- Age
- Ethnic origin
- Genotype for target enzyme (VKORC1)
- Diet and lifestyle factors
What is the target enzyme for coumarin anticoagulants including warfarin?
Vitamin K epoxide reductase
What polymorphisms in VKORC1 may be relevant to dose requirement?
- Homozygous A-1639 genotype associated with reduced warfarin dose requirements by up to 3mg/day
- CYP4F2 contributes to vitamin K metabolism
What does the regression equation for warfarin dose account for?
CYP2C9/VKORC1 genotype, age, and height
What was the outcome of the EU-PACT clinical trial regarding genotyping for warfarin dosing?
Genotyped group showed INR closer to 2.5 more consistently and spent higher percentage of time in the therapeutic range
What is required prior to initiating treatment with abacavir?
Genetic testing for HLA-B*57:01 allele
What percentage of patients develop hypersensitivity reactions to abacavir?
Approx. 5%
What is the risk associated with the HLA-B*57:01 allele when treated with abacavir?
Increased risk for abacavir hypersensitivity reactions
What is the significance of the Mallal study related to HLA-B*57:01?
Confirmed the association of HLA-B*57:01 with abacavir hypersensitivity
What is the prevalence of HLA-B*15:02 in the Han Chinese population?
> 15%
What pharmacogenetic testing is recommended before starting carbamazepine?
Test for HLA-B*15:02 alleles
What is the drug metabolized mainly by CYP2D6 that requires genotyping before prescribing?
Eliglustat
What is the common genetic defect associated with cystic fibrosis?
Delta F508
What is the indication for Atezolizumab?
Treatment of adult patients with locally advanced or metastatic urothelial carcinoma after prior platinum containing chemotherapy
What is the significance of the G-1639A and C1173T polymorphisms in CYP4F2?
Associated with lower warfarin dose
What does the Predict-1 study show about HLA-B*57:01 screening?
Reduced the incidence of suspected hypersensitivity reactions from 7.8% to 3.4%
