LEC45: Pharmacogenetics and Pharmacogenomics

Question 1

what is personalized medicine

Answer 1

use of genomic info to tailor therapy to an individual’s genotype

Question 2

pharmacogenetics?

phamacogenomics?

Answer 2

pharmacogenetics: study of drug response in realtion to genetic variation in specific candidate genes
pharmacogenomics: study of drug response in relation to genetic variation in the entire genome

Question 3

what benefit might personalized medicine confer?

Answer 3

many drug classes are ineffective for a large percentage of the population

due to many factors - genetics, age, race/ethnicity, weight, gender, concomitant diseases, concomitant drugs, diet, social factors

if could consider these factors together and treat based on them, = peronslized medicine

Question 4

clinical potential benefits of pharmacogenetics?

Answer 4

1) improve drug selection - predict responders vs. non-responders
2) predict adverse drug reactions (ADRs)
3) dose adjustment for maximum efficacy & safety
4) decrease health care costs

Question 5

why consider genetic variation re: personal response to drug?

Answer 5

in order to separate out individuals who’re likely to benefit from a drug without adverse effects from whose who will suffer adverse effects, w/ or w/o clinical benefit

Question 6

what are pharmacokinetic actions that are associated w/ drug metabolism re: a gene’s genetic variation?

Answer 6

ADME:

absorption, distribution, metabolism, eliminatino

Question 7

which genes influence drug pharmacodynamics?

Answer 7

genes involved w/ receptor interactions, ion channel interactions, enzyme interactions, signaling pathway interactions, immune system interactions

Question 8

what are all possible parts of gene processing that explain how pharmacogenetic gene expression coudl be impacted?

Answer 8

1) promoter expression
2) missense/nonsense/splice enhancer
3) splicing defect
4) splice enhancer
5) frame shift/premature truncation
6) translation/miRNA

Question 9

what pharmacokinetic processes fall within Phase I and Phase II?

Answer 9

Phase I: oxidation, reduction, hydrolysis

Phase II: conjugation by biotransformative processes - acetylation, glucoronidation, sulfation, methylation

Question 10

what are the cytochorme P450 (CYP450) enzymes?

Answer 10

large, diverse, polymorphic class of enzymes (hemoproteins) that catalyze hydroxylation (Phase I) and other metabolic reactions

both exogenous & endogenous compounds

are major enzymes involved in drug metabolism, bioactivation

highly polymorphic- lots of variance- and >50 diff CYP450 genes, pseudogenes exist

Question 11

what is nomenclature for CYP450 enzymes?

Answer 11

star allele system:

“star” (*) designated for allels for each polymorphic variant identified

*1 = enzyme activity of the most common, wild-type allele

*2-28 = higher number = less prevalent allele

Question 12

what genetic variations contribute to thereduced activity of the non wild type * alleles of CYP450?

Answer 12

mutational types of variation: promoter, missense, nonsense, frameshift, copy number variant, etc

Question 13

what are the different phenotypes of enzymatic activity?

Answer 13

1) Extensive Metabolizer: inherits both *1, wild type, alleles or 1.5; has high functioning enzyme, metabolizes quickly
2) Intermediate Metabolizer: inherits 1 *1, wildtype, and 1 non WT allele, less well-functioning
3) Poor Metabolizer: inherits 2 non-*1 alleles, nonfunctioning b/c of loss of function or deletion

Question 14

what was the CYP2D6 enzyme do?

Answer 14

metabolizes 20-25% of all medications!

antidepressants, antipsychotics, antiarrhythmics, opiates, antiemetics, B-adrenoceptor blockers, tamoxifen..

Question 15

what is a CNV?

Answer 15

copy number variant

is full gene deletion and duplication

i.e. with CYP2D6, if have an extra copy, get ultrarapid metabolism

Question 16

what is distribution of poor metabolizers worldwide?

Answer 16

frequency of variants varies widely depending on ethnicity, genetic background

thus want to characterize genetic variations in local ppulations for dosing recommendations

Question 17

what gene is associatedf w/ warfarin?

what does warfarin dosing recommendations demonstrate?

Answer 17

gene: 1639G>A of VKORC1 gene
warfarin: anti-clotting agent

“A” allele causes increased drug sensitivity by reducing txn of VKORC1, is present at low frequency in African populations, intermediate frequency in Europeans, high frequency in East Asian pops

suggested starting dosages reflect these regional differences in gene frequencies

Question 18

what does warfarin do?

Answer 18

oral anticoagulant for prevention of thrombosis and embolism and especially atrial fibrillation

prolongs clotting time by impairing syntehsis of Vitamin K-dependent clotting factors

has a very narrow therapeutic index

Question 19

what is dangerous about warfarin?

Answer 19

has a very narrow therapetuc range:

there are significant interindividual differences in response to drug, there is narrow window btwn effective dose and dose that leads to adverse effects due to an increased risk of bleeding or stroke

must frequently monitor international normalized ratio blood test (INR) to measure degree of anticoagulation

Question 20

what is safe therapeutic range for warfarin?

Answer 20

mean dose: 2-3

Question 21

what influences warfaring dosing variability?

Answer 21

age, gender, drug interactions, diet (vitamin K), alcohol, smoking, genetics (pharmacokinetics & pharmacodynamics)

Question 22

what is pathway of warfarin activation?

Answer 22

CYP2C9 metabolizes warfarin

warfarin inhibits VKORC1 of the Vitamin K reduction cycle

this varies based on VKORC1-1639G>A polymorphism - less VKORC1 pt has, less warfarin needed

so if account for genotype at CYP2C9, can find correlation btwn enzymatic activity and weekly warfarin dose requirement

if have LOF in CYP2C9, warfarin will be around for longer, need less of drug to get to target

Question 23

how does warfarin dosing vary re: CYP2C9 VKORC1 genotype?

Answer 23

patients w/ non-wildtype alleles need less weekly dose of warfarin

Question 24

what factors besides allele genotype impact warfarin dosing?

Answer 24

clinical - age, BMI, etc - and genetic variables both

Question 25

what is clopidogrel?

Answer 25

anti-clotting agent commonly used for prevention of clot formation after stent placement in heart for narrowed arteries

Question 26

what polymorphism was identified as being less effected b clopidogrel?

Answer 26

CYP2c19 *2 allele, a missense polymorphism

individuals w/ CYHP2C19 *2 didn’t have same reduction in aggregation in response to clopidogrel as *1 homozygotes

also more likely to have cardiovascular ischemic event or death during 1 year follow up

polymorphism also shown in GWAS findings re: clopidogrel response

Question 27

how is pharmacogenetic information being integrated clinically?

Answer 27

clincian education about implications of drugs’ dosage given different genetic compositions of patients

efforts like clinical pharmacogenetics implementation consortium (CPIC)

gives info about when have high toxicity risk and high efficacy risk for patients re: certain drugs

Question 28

challenges to clinical pharmacogenetics?

Answer 28

1) genotype/phenotype relationships aren’t always clear cut; majority of drug responses are complex
2) drug development may be negatively influenced
3) cost - genotyping can be expensive
4) need results fast - should be at point of care, or pre emptive testing?