Exam 2 lecture 8 & 10 Flashcards
variability in patient responses (asthma)
- disease severity/type
- treatment adherence
- comorbidities
- other meds (interaction)
- environmental triggers
up to ___ of asthma patients treated using current guidelines are not controlled
25%
polymorphism affecting asthma patients
beta-receptor- target of beta 2 agonist (albuterol salmeterol)
mutations affect receptor susceptibility to
down-regulation in response to beta 2 angonists and NOT drug binding
patient response to SABA
gly/gly group- improved with albuterol only
arg/arg group did better on placebo
patient response to LABA- salmeterol/placebo
ARG/ARG lung function decreased in both trials w/ salmeterol
patient response to LABA while on ICS
- both groups improved with salmeterol compared to palcebo
patient response to LABA (blacks)
those with arg/arg mutation did not do better
- says there is clearly genetic factors
summary of impact of beta-receptor polymorphisms
- ARG 16 associated with adverse outcomes with regular use of SABA
- ARG16 does not appear to adversely affect outcomes with LABAs when used with ICS***
5-10% of asthma patients have reduced responses to
glucocorticoids
genetic polymorphisms in glucocorticoid
receptors and in regulatory feedback loop
glucocorticoid receptor polymorphisms:
some can decrease efficacy and some can increase it
corticotropin releasing hormone receptor 1 role
regulation of the endogenous cortisol level
study 1 (ADULT)
adults
treated w/ ICS for 8 weeks
study 2 (CAMP)
children
ICS, nedocromil or placebo for 8 weeks
GAT mutation
patients with GAT did much better then wild type in response to ICS
what is the significance of GCCI1?
- glucocorticoid induced transcript 1
- expressed in lung and immune cells
- glucocorticoid therapy may increase expression
- possible marker of apoptosis
- mutations that < GLCCI1 expression may decrease response to ICS
what percent of the population has GLCCI1 mutations
16%
CRHRI
GAT mutation associated with increased efficacy
GLCCI1
TT mutation associated with decreased efficacy
inter-individual variability in
- development of diseases
- drug efficacy
- drug toxicity
overall therapy response
50%
most common ADRs caused from
- diuretics
- opioids
- anticoagulants
applications for PG
- identify basis of inter-individual variability
- enable tailoring of therapy to patient/disease genetics
- identify novel treatment approached
genotyping
define a biologic population based on genetics (DNA sequence)
phenotyping
define a biologic population based on an observable physical or biochemical characteristic (Probe metabolites)
genes commonly tested
- invader UGT1A1 (genzyme)
- HER2
- HLA B*5701
microarrays commonly tested
- ampliChip (Roche diagnostics)- 2 genes (CYP2D6 & 2C19)
- DMET Plus (Affymetric)- 230 genes including P450’s, drug transporters, etc
- oncotype Dx (Genomic health)- 16 genes associated with breast cancer
microarray genotyping have up to ____ genes on one chip
500,000
other factors affecting PK & PD
- unidentified genetic factors
- environmental factors
- interactions w/ drug, food or disease
clopidogrel is metabolized by what enzyme?
CYP2C19
intermediate metabolizers of clopidogrel have
53% increase in risk of death from CV events
poor metabolizers of clopidogrel have
> 3.5- fold increase in risk for second CV event
CYP2C19 polymorphisms are associated with
resistance to clopidogrel
- EM: normal dose
- IM: higher dose or alternative agent
- PM: alternative agent
alternative agent for PM of clopidogrel
prasugrel (Effient)
Abacavir is a highly effective NRTI but
2-9% iodsyncratic hypersenitivity reaction (HSR)
- dose dependent
- not predicted in animal models
- onset during first 6 weeks: fever, rash, GI and respiratory symptoms
- potentially fatal
decreased HSR risk with albacavir in
African americans
HSR gene for abacavir reaction
HLA-B*5701
traditional chemotherapy
doxorubicin, cyclophosphamide, paclitaxel, docetaxel
targeted chemo
trastuzumab
hormonal chemo
tamoxifen, aromatase inhibitors
tumor HER2 over-expression
- 20% breast cancer
- traditionally associated with poor prognosis
- not inherited
50% of new cases of breast cancer are
estrogen receptor (ER) positive, lymph node (LN) negative
80% of breast cancer adequately treated with
surgery +/- radiation and hormonal therapy
chemo can be beneficial for breast cancer
- 25% relative risk reduction for recurrence
oncotype Dx
- 21 gene assay: 16 cancer genes & 5 house keeper genes
- predictive of recurrence and survival
low risk
chemo not beneficial
<18
High risk
chemo beneficial
>30
intermediate risk
unclear
18-30
HER2 status
trastuzumab
ER status
tamoifen or aromatase inhibitor
depending on cancer stage, grade, comorbidities, & clinician experience: oncosype DX
traditional chemo
