what is personalized medicine
use of genomic info to tailor therapy to an individual's genotype
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
what benefit might personalized medicine confer?
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
clinical potential benefits of pharmacogenetics?
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
why consider genetic variation re: personal response to drug?
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
what are pharmacokinetic actions that are associated w/ drug metabolism re: a gene's genetic variation?
absorption, distribution, metabolism, eliminatino
which genes influence drug pharmacodynamics?
genes involved w/ receptor interactions, ion channel interactions, enzyme interactions, signaling pathway interactions, immune system interactions
what are all possible parts of gene processing that explain how pharmacogenetic gene expression coudl be impacted?
1) promoter expression
2) missense/nonsense/splice enhancer
3) splicing defect
4) splice enhancer
5) frame shift/premature truncation
what pharmacokinetic processes fall within Phase I and Phase II?
Phase I: oxidation, reduction, hydrolysis
Phase II: conjugation by biotransformative processes - acetylation, glucoronidation, sulfation, methylation
what are the cytochorme P450 (CYP450) enzymes?
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
what is nomenclature for CYP450 enzymes?
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
what genetic variations contribute to thereduced activity of the non wild type * alleles of CYP450?
mutational types of variation: promoter, missense, nonsense, frameshift, copy number variant, etc
what are the different phenotypes of enzymatic activity?
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
what was the CYP2D6 enzyme do?
metabolizes 20-25% of all medications!
antidepressants, antipsychotics, antiarrhythmics, opiates, antiemetics, B-adrenoceptor blockers, tamoxifen..
what is a CNV?
copy number variant
is full gene deletion and duplication
i.e. with CYP2D6, if have an extra copy, get ultrarapid metabolism
what is distribution of poor metabolizers worldwide?
frequency of variants varies widely depending on ethnicity, genetic background
thus want to characterize genetic variations in local ppulations for dosing recommendations
what gene is associatedf w/ warfarin?
what does warfarin dosing recommendations demonstrate?
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
what does warfarin do?
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
what is dangerous about warfarin?
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
what is safe therapeutic range for warfarin?
mean dose: 2-3
what influences warfaring dosing variability?
age, gender, drug interactions, diet (vitamin K), alcohol, smoking, genetics (pharmacokinetics & pharmacodynamics)
what is pathway of warfarin activation?
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
how does warfarin dosing vary re: CYP2C9 VKORC1 genotype?
patients w/ non-wildtype alleles need less weekly dose of warfarin
what factors besides allele genotype impact warfarin dosing?
clinical - age, BMI, etc - and genetic variables both
what is clopidogrel?
anti-clotting agent commonly used for prevention of clot formation after stent placement in heart for narrowed arteries
what polymorphism was identified as being less effected b clopidogrel?
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
how is pharmacogenetic information being integrated clinically?
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
challenges to clinical pharmacogenetics?
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?