Term
|
Definition
- SLC: 50 families, no ATPases --> ion gradiates (uptake AND efflux)
- ATPases: ABC transporters!! ONLY efflux
- approx 25 transporter families are important for drug trnasport |
|
|
Term
OATP1B1
substrate (endog/drugs), where/fn, |
|
Definition
- SLCO1B1
- endog Substrates: bile salts, organic antions, THYROID, sulf/glucuronide conjugates
- drug substrates: antibact, anticancer, STATINS, ARBs, Digoxin,
- Liver basolateral: uptakes into the hepatocyte |
|
|
Term
|
Definition
*5 allele: T521C
those w/ CC = increased myopathy (TT lower incidence)
you'd want to lower dose |
|
|
Term
|
Definition
- SLC22A1
- Uniporter : FACILITATED DIFFUSION -- transports ORGANIC CATIONS
- Endog Substrates: guanidine, choline, ACH, NE, progest, PGE2
- Drugs: Atropine, METFORMIN< verap, acyclovir |
|
|
Term
|
Definition
| - Dep on OCT1 to get into hepatocytes (where metformins target is) |
|
|
Term
| ABC Multidrug Transporters |
|
Definition
- ABC = ATP Binding Cassette: 7 families A -G
- Primary ACTIVE transporters -- against ec gradients using ATp hydrolysis
- EFFLUX ONLY!!!! Takes substrates out of cells |
|
|
Term
MDR1
- type, location, substrates |
|
Definition
- ABCB1 or Pgp
- differs from SLC bc huge NBD (nucleotide binding domain)
- EFFFFFFFFLUX ---- protect body from toxicity!!
- on apical side of epithelial cells
- endog: STEROIDS, PLs, ILs, peptides
- Drugs: ... a ton lol. |
|
|
Term
|
Definition
-Important on luminal membrane
- so when theres a mutation in MDR1, theres less efflux so incr in digoxin concentrations |
|
|
Term
| Drug xport in small intestine |
|
Definition
- Apical (lumen side) has SLC (influx) and ABC (efflux)
- Basolateral: primarily just ABC (efflux) - from enterocyte to blood |
|
|
Term
|
Definition
- Basolateral: uptake by OCT/OAT, and efflux by MRP
- Apical: SLC/ABC transporters, but has PEPT1,2 which reabsorbs drug back into the enterocyte |
|
|
Term
CODEINE
metabolism, 2d6 varaints/prevalence |
|
Definition
- 2D6 metabolism into active ---- morphine! (codeine is a prodrug w/ no analgesic act)
- 4/5 caucasians, 10 is asians, 17 is african americans |
|
|
Term
| Codeine and Metabolizer Status |
|
Definition
- More than 2 copies of WT alleles -- ULTRA metab -- se (sed/constipation) high morphine
- 2 copies WF -- Extensive -- expected
- 1 inactive 1 redced or 2 reduced (IM): drugs in btwn EM/PM... optimal dosing?
- 2 copies of inactive: POOR metab -- higher than expected CODEINE.. not enough pain relief |
|
|
Term
|
Definition
- w/ UM u get more morphine
- you don't see the converse of codine tho - you would think if you were a poor metabolizer ud have high. but its actually unchagned (could be do to limitations of study) |
|
|
Term
| Codeine in neonates from preg/breastfeeding |
|
Definition
w/ moms who are ULTRA METABs - respiratory depression/sedation
- high amt of morphine transferred in breast milk
UM: high in ethiopians (29%) but not super prevalent
recommendations
- Morphine, HM OM are all ok
- TRAMADOL AND OXYCODONE ARE NOT |
|
|
Term
| 2D6 Pgx testing and clincal rec for codeine therapy |
|
Definition
- not required to start codieine
- but recommendations regarding dosing/selection of codeine based on genoetype are published!
-UM: avoide codine due to potential for toxicity
- PM: avoid codeine use due to lac of efficacy |
|
|
Term
| Tramadol and Oxycodone mtabolism |
|
Definition
- metbaolized by 2D6 to O-desmethyltramadol = ACTIVE (greater analgesic/toxicity risk)
- Oxy is made into oxymorphone --- 3x5 more u opioid receptor affinity than M and OC (oversedation and resp depression) |
|
|
Term
|
Definition
all g protein coupled
Mu: analgesia, euphoria, respriatory depression, phys dep --- agonists are endorphines
Kappa: mixed action agonist and anaalgesia of spinal cord, sedation, dysphoria
Delta: maybe analgesia |
|
|
Term
|
Definition
Gene = OPRM1
Variant = 118 A > G
Prevalence: 10-15% caucaisnas, ASIANS IS 50%! |
|
|
Term
| Mu opioid vairant functional effect |
|
Definition
AA = homozygous
AG and GG = REDUCED MU RECEPTOR EFFICACY UPON AGONISM AND REDUCED EXPRESSION
- causes methylation at position 117... (this INACTIVATES a gene)
your mu receptor just sucks |
|
|
Term
| Mu receptor variant: anaglesic/side effects |
|
Definition
less analgesic, but less side effects when it came to respiratory depression
N/V... made no diff
pruritis had conflicitng data |
|
|
Term
|
Definition
cost has gone down over the yrs
moores law = computes power being doubled over 2 yrs
technology is measured against this... so if its faster than moores law its a good thing |
|
|
Term
| Goals of genomic info in med practice |
|
Definition
- detect hereditary predisp of dz
- gene based therapies
- safety
- cost effectiveness |
|
|
Term
|
Definition
economic outcomes
clinical outcomes
humanistic outcomes |
|
|
Term
|
Definition
disorder/setting
- analytic validity: quality control, analytic speci/sensitivity
- clinical validity: clin sp/sens, prevalence, penetrance
- clinical utility: how effective is this intervention? economic evaluation
- ELSI: ethical legal social implications
*clin utility and validity is what we struggle w most |
|
|
Term
| Pharmacogenomic test requirements |
|
Definition
- accuracy: sp/sens
- cost: of test and related serv
- timeliness; time frame to get results
- alt: other approaches to drug sel and dose opt? |
|
|
Term
|
Definition
- Prevalence: how many variants? how many pts to tst? pos/neg predictve powers of the test?
- Penetrance: rel btwn variant and drug response, relative risk of AE? probability of a drug response? |
|
|
Term
| Clinical Outcomes in Pgx Testing |
|
Definition
- prealence and risk: how commone is the AE? how common is drug non response?
- outocmes/economic impact - how expensive is the AE/drug non response? what is the impact on QOL? |
|
|
Term
|
Definition
mpas out exactly what u wanna do
you have a decision node, then a chance node, and then a terminal node |
|
|
Term
|
Definition
- simplest to perform
- assumes no differences in efficacy (outcomes are NOT measured - unlike all the other designs) so u can only use if outcomes same for both interventions. |
|
|
Term
|
Definition
- tells you outcome in MONETARY terms
- Can use w/i healthcare and across sectors of economy
- BUT weakness --- no accepted by health care deicision makers
- assess intitial investment of intervention vs its benefits: xform benefits to cost
NET BENEFIT = TOTAL BENEFIT - TOTAL COST
- cost benefit ratio |
|
|
Term
|
Definition
CBR = Total benefit/total cost
CBR >1 = good investment (total benefits outweigh cost)
<1 = dont doooo it
= 1 break even |
|
|
Term
|
Definition
outcome is measured in CLINICAL terms
- Relevant for clincians
- BUT cant compare interventions across dz areas using dz specific end points
- cant tell you QOL
- assess diff in total cost btwn 2 interv/diff in efficacy to give ICER (incremental cost for each addition unit of benefit achieved)
ICER = (total cost A - total cost B)/ (total effic A - total effic B)
efficacy = cure rate |
|
|
Term
| Cost effectiveness plane! |
|
Definition
effect on x, cost on y
NW: dominated in which treatment less costly but less effetie
SE: dominant: more effet w/ less cost!
NE: most costly but more effective |
|
|
Term
|
Definition
- outcome is measured based on QUALITY ADJ LIFE YEARS (QALY)
- allows u to incorp QOL, comparable across dz areas/interv (cost effectiveness did NOT)
- weakness is requires eval of pt pref (hard to interpret)
- quantifies morbidity and mortality
- value btwn 0 (deaht) and 1 (perfec health)
QOL = life years saved x utility for each year saved ! |
|
|
Term
|
Definition
Burlington Northern Sante Fe Road
- tested employees for genetic cond for carpel tunnel syndrome, but testing did other conditions too (employees didnt know)
- threatend w/ termination if they didnt comply
- Equal employe opporutnity commsion (EEOC) filed lawsuit against BNSF
said unlawful and cause discrimatinion - Americans with Disabiltiies Act bc test were not job related
stopped testing |
|
|
Term
|
Definition
indiv w/ known genetic disorder is treated diff by company
GINA: Genetic Information Nondiscrimatio Act of 2008 protects us! w/ health ins and employment |
|
|
Term
|
Definition
ie... HIV/AIDs neg connotations as immoral predatory and dangerous
patients as well as those related to them
Def = labeling based on feature
indiv feels isoalted hopeless depressed
pgx testing can reveal sim neg connotations and public perceptions |
|
|
Term
| Privacy and Confidentiality |
|
Definition
- methods to minimize: deidentified subject data, passwords, limtiing access (all suck this doesnt work)
HIPAA: health ins portability and accountability act
- protects PHI
- BUT this DOES NOT APPLY TO INDIV WHO SEE K PRIV HEALTH INS IN INDIV MARKET |
|
|
Term
| Ownership of data/samples (legal issue in pgx) |
|
Definition
- subject donor: its their property right
instituion conducting research: they own it for research purposes
or investigator owns it |
|
|
Term
|
Definition
Moore sued claiming depriv of prop interest, lack of adequate informed consetna dn breach of fiduciary duty = legal duty to be aware of individuals interest
specimien was collected... and results of research led to patent application
court ruled favor of Regents:
- saying that he didnt have right of ownership.
NOW theres legal precendence (informed consent) |
|
|
Term
Intellectual property (legal issue)
PATENTS |
|
Definition
Patent: provides inventor right to manuf, use, sell
qualifies if...... NUO ---- novel, useful, and not obvious
20% of human genes are under US patents |
|
|
Term
|
Definition
AGAINST gene patents: they are naturally occuring - to be disc no invented
FOR gene patents: isolating DNA is NOT natural
- diamond vs chakrabarty
- ACLU and myriad genetics |
|
|
Term
| Diamond v Chakrabarty (US Supreme court case) |
|
Definition
- Chak was employee for General E (GE) - made gen mod bacterium that can breakdown crude oil to treat oil spills
- patent was REJECTED bc saying living things are not patentable
- appeal to US court: ruled in favor of Chakra
- then went to Supreme Coourt: where patent was granted because said the methodology is patentable |
|
|
Term
|
Definition
ACLU = american civil liberties union
-lawsuit againt MG for patent on BRCA1 and BRCA 2 (breast/ovarian cancers)
MG owns 7 patents against it -- commecial test BRCAanalysis
ACLU argued that BRCA genes ar product sof nature
Myriad: cited D v C
SURPRISE RULING: COURTS INVALID THE PATENTS
APPEALS: overturned; said that they are patentable |
|
|
Term
|
Definition
| - America Invents Act (fir st to invent now first to file) - competition! |
|
|
Term
| Disclosure of ancillary information |
|
Definition
def = addit info pertaining to predisp of dz, prognosis or info relevant to other drugs in which indiv is not currently seeking treatment
issue?
- pgx generates this info, no consensus to communicate this info
should it be returned to the pt/parents
Thoughts:
- PUBLIC - md should disclose it , want to incr knowledge of fam hist
- HCP: MDs felt obligate
- Geneticists: disclosure is not always req due to complexities of genetic traits |
|
|
Term
| Pharmacists; reliability of disclosing info? |
|
Definition
Posssssibly... at risk under OMNIBUS BUDGET RECONCILIATION ACT of 1990
- Breach of duty: if pharm is aware or learns pt is a genetic vairant adn is at risk of AE and does not inform!
- 2000 insitutie of medicine report: raised awareness of pharm RESP and liability risk in ensuring safe/appropriate treatment
- pharmacetucial companies , physicians, insurance companeis should also all be liable (failrue to warn, failure to rder test, failure to pay/cover)
leverage for litigation: could an AE from a drug due to genetic variant that shoudl be tested prior to staritng a drug? |
|
|
Term
| Cassidy v SmithKline Beecham (SKB) |
|
Definition
Scneider: particpated in citys health dep to test vaccine aainst lyme... paralyzed long term effects of arthritis, numbness, tingly
SKB FAILED TO WARN HCP/General public
1/3 were predisposed to autoimmune arthritis!!!! |
|
|
Term
| LYMErix vaccine and the Dz |
|
Definition
tick borne infn... NOT an autoimmune dz - Borrelia burgdorferi (spirochetal)
due to deer ticks
* most common vector borne human dz
LIMERIX: has rebom surface protein called outside surface protein (OspA)
- body dev immune resposnset to OspA and thus to bacteria |
|
|
Term
| Variatn for LIMERIX Vaccine |
|
Definition
- HLA type DR4+ or HLA - DRB1*0401
30% of general pop have this --- higher risk for dev chronic treatment-res arthritis bc they produce high conc of OspA in synovial fluid!!
- if they are HLA DR4+ and u give them vaccine... immune response to Osp would occur. but the immune response would cross react.. leading to autoimmune
(causality was difficult to demonstrate)
Screen for HLADR4... if + then dont give vaccine |
|
|
Term
| Sheller Ludwig & Baily Vs SKB |
|
Definition
SKB showed studies no diff in AEs btwn vaccinated and vaccinated subjects
-SKB removed vaccine from market: denied LYMErix casued harm, said to settle it based on economic conerns which is whythey removed it |
|
|
Term
| Race/Ethnicity (Social issue) |
|
Definition
2C19*2 and 2C19*3 = highe rin asians
HLA-B*1502 is higher in asians
issues
- pgx testing may stratify patients (subjects to genetic discrim/stgimaz)
- health disparities and accessibility to pgx testing
- race may be exclusion criteria for study particip in drug developmen |
|
|
Term
| National Revitalization Act of 1993 |
|
Definition
| mandated inclusion of racially identified groups into research |
|
|
Term
| examples of single gene disorders |
|
Definition
- butyrylcholinesterase def (anesthesia)
- malignant hyperthermia (ryr anesthe)
- seizure disorders - nicotinic receptor mutations
- CFTR |
|
|
Term
| cousins of cholinergic molecules |
|
Definition
- abhydrolase fold proteins: acetylcholinesterase and butyryolchilineasterase
- pentameric cys loop receptors: nictonic and 5HT3, y amino butyric acid and lgycine receptors
- g protein linked
- presynaptic transport proteins: choline and ach uptake |
|
|
Term
| butyrylcholinesterase deficiency |
|
Definition
- succinaylcholine apnea
succinl is given by infusion in which BE should hydrolyze it. but bc deficient u get too much ACH + too much depolarization
- BE is used to hydrolize esters (detoxify food) |
|
|
Term
|
Definition
- SR ca channels RyR receptor -- mutations lead to triadic junction of Ca release -- generates ATP hydrolysis and heat energy
- DANTROLENE = antidote (blocks release) (use limited by chronic liver conditions) |
|
|
Term
|
Definition
Autoimmune dz in which antibodies are made to nicotinic receptors... jmuscles are weak
- antibodies block/alter/destroy receptors for ACh... so px the muscle contraciton from occuring |
|
|
Term
|
Definition
- Catalytic care: Glu His (imidazole) Ser
- only has 3 mutations: R3Q, D134H, H332N bc its essential for life
- Expressed in red cell.. deleterious mutation = loss of indnividual |
|
|
Term
|
Definition
- unlike AChE... its only function really is when u give drugs and need it to break down
it can hydrolyze esters because its rendered as a STRONG NP -- IMIDAZOLE IN HISTADINE
- |
|
|
Term
| Ligand gated pentameric ion channels |
|
Definition
- nicotinic 5HT3 as EXCIT, gaba/glycine as INHIB
- nicotoinic: skeletal has a12byd (embryonic) a12byed (maternal)
- |
|
|
Term
| congenital myasthenic syndromes |
|
Definition
- defect in CHAT: responsible for synthesis --- so you dont make enough ACh (weak )
- defects in AChE: lower bc less ACh is in the synapse |
|
|
Term
| Kinetic abnormalities of AchR (Myasthenic syndromes) |
|
Definition
- most treatable: just functional changes in which its a slow or fast channel
1) channel doesnt close fast enough: stays open too long
continuous DP... so you don't get rapid stimualtion
2) closes too fast
3) theres not enough receptors
hyperactive channels can be treated w/ channel blocking agents |
|
|
Term
|
Definition
- use structure/preomics to understand genetics/genomics
- aply to non-synoymous cSNPs |
|
|
Term
| structure/fn of a,B- hydrolase fold family |
|
Definition
Cell adhesion: Neuroligan
Catalytic act: Ache and Bche
Hormone prod: Thyroglobulin |
|
|
Term
|
Definition
- similar in struct w/ cholinesterase so molecules fold in same way
- Neurexin: presynaptic partner that associates w/ it
- mutation leads to ASD |
|
|
Term
| Autism Spectrum Disrorders |
|
Definition
- strong genetic background w unknown env influences
(viral exp, valproic acid, mercury, organophosphates)
sx
- social impairment: no social reciprovcity, eye contact
- verbal and non verbal comm abnormalities
- stereotyped behaviors (restricted repertoire of act, interests |
|
|
Term
| fetal development timeline + significance |
|
Definition
- dev stages have diff rnage of gene expression
- 1 in 33 babies in the us have a birth defect
- want to ID babys risk of dv certain diseases |
|
|
Term
| Gene expression changes with time in fetus |
|
Definition
CYP3A7 declines quickly within first wk of birth
CYP3A4/5 increases at one week of age
UGT: (metabolizes bili... which babies have a lot of)
levels incr from 1-100% by 2 weeks
Cyp2D6 and Mom; if moms ultra metab and takes codeine.. baby can be poisoned w/ morphine |
|
|
Term
|
Definition
1) kids not small adults: cant just use half of adult and weight based dosing isnt perfect either
2) BA of drugs is also not same for kids as for adults
3) genotypes dont always correspond to phenotyeps in kids since they have diff dev stages |
|
|
Term
|
Definition
kids infected through mom/breastfeeding -- because of this and babys CNS is still growing at birth, HIV load is higher in children and they have a faster progression (adult prog varies
higher CD4+ cell count, and possibly a better prognosis if we treat them earlier |
|
|
Term
| MDR1 Gene and HIV in kids |
|
Definition
MDR1 = for pgp = pumping drugs out
Nelfinavir (protease inhibitor) = substrate for it... levels affected based on polymoprhisms;
CC is normal: AA > Cauc > Hispanic
C/T: HIS > AA > Cauc -- more likely to control (less mdr1 so less efflux) their HIV load
T/T Homozygous: Cauc >>> AA/Hispanic
so w/ less MDR1--> less pgp, u have more drug in plasma so less viral load |
|
|
Term
|
Definition
- Nelfinavir is metab by 2C19 to the M8 metabolite (inactive)
G/G wild type: fully functional.. highest M8:NFV ratio
higher ratio = more metab = less active drug = higher HIV load
G/A: hetero: non functional protein
A/A homozygous: lowest ratio --- less 2C19 so less nelfinavir metabolism so more active drug and higher HIV suppression
Hispanics and blacks have most striking diff in NFV clearance w/ G/G vs. G/A |
|
|
Term
|
Definition
-Access: availability, providers, insurance coverage
-Feasibility: turnaround time, sensitivity/specificity, efficiency
-Cost: genetic test, dz mgmt, counseling
-Progressive Evidence:cost effectiveness, lacking long term data, predictive value, expertise, etc. |
|
|
Term
| Challenges w/ Psycho-pharmacotherapy |
|
Definition
-Dz pathways not elucidated for most psychiatric disorders
-Theories of how drugs work based on serendipitous discovery (don't fully understand how tx work)
-Tx based upon trial and error for most disorders (2/3 pts don't respond to initial tx)
-High rate of non-response and relapse w/ most psychotropic medications |
|
|
Term
| Limitations w/ Neuropsychiatric PGx Studies |
|
Definition
-Candidate genes vs GWAS studies
-Clinical setting "noise"
-environmental factors
-cross-over btwn dz states and Tx options (1 drug potentially wide range of effect on mutiple dzs)
-Tx duration (most drugs take 6-8 weeks to work)
-Response assessment methods (lots of rating scales exist, but can be subjective)
-Phenotypes not defined and based upon subjective pt reports (diagnosis often subjective too)
-Replication of results |
|
|
Term
|
Definition
-33 medication combinations in neurology and psychiatry
-info taken from FDA approved drug labels
-Of the drugs w/ biomarkers on FDA table, 20% are neuropsychiatric drugs |
|
|
Term
| Antidepressant Med PGx studies |
|
Definition
-Clinical response: serotonin transpoter
-tolerability/ side effects: CYP450 enzymes |
|
|
Term
| Why do we need PGx for antidepressants? |
|
Definition
-42% variance in anti-depressant response associated w/ genetic variation
-only 30% achieve symptomatic remission (Tx goal) w/ first treatment
-difference in response show patterns w/in families and ethnic groups
-PGx may help w/ drug selection and AE prevention |
|
|
Term
|
Definition
-presence of TPMT *3a, *3c, or *2 : causes DEF of TPMT.. so less clearance of the methylated metabolites --> increase of toxic metabolite in alternate pathway --> MYELOSUPPRESSION and HEPATOTOXICITY
3a is common in caucasians (1-10%)
3c is asians and african americans |
|
|
Term
| Non synonymous SNP TPMT : 3A |
|
Definition
615 G -- A and 874 A -- G
result is an increase in 6 TGN and decr in 6 MeMP
so you get more of an active metabolite leading to toxicity/efficacy |
|
|
Term
| Mercap clinical app and pgx testing |
|
Definition
no efficacy lost in giving dose reduced in those w/ low/absent TPMT
toxic: those that were homozygous and given standard had hem toxicity
- RECOMNED TO SCREEN FOR 3A 3C and 2 !!
homozygous: dose reduction
heterozygous : monitor for toxicities |
|
|
Term
|
Definition
gold standard endocrine therapy for pts w/ ER+ PR+ breast cancer (SERM)
made into endoxifen thru 2D6!! which is active (clinical & toxic effects)
decr enzyme activity: *10, 17, 41 = IM *1/*4
loss of enzyme: *3, 4, 5, 6 = PM *4/*4
incr enzyme act: *17x2, 41x 2 = EM *1/*1
so incr in enzyme = more active = more drug works, better outcomes :) |
|
|
Term
| txamofein clinical relevance/rec |
|
Definition
No testing recommendation!!! [conflicting study data]
Just FYI:
CYP2D6 variant prevalence:
*4 = 20-25% caucasian
*10 = 35-55% asian
*17 = 10-43% african american |
|
|
Term
|
Definition
camptothecin class of topoisomerase
activity against colorectal and SCL cancer
SE = diarrhea, neutropenia, vascular syndromes
UGT1A1*28 (7 repeats instead of 6)---- dose reduction in those homozygous for this bc drug isnt as cleared [SN-38 toxic metabolite]
Improved irinotecan toxicity profile w/ CYP3A activity |
|
|
Term
|
Definition
considered a proto oncogene
a GTPase
- turn on: binds GTP -- cell differetiation
-- turned off = GDP - no signals
kras usually turns on when EGFR is turned on
always turned on w/ codon 12, 13 or 61
mutation NOT recommended for risk assessment |
|
|
Term
|
Definition
- Tyrosine kinase receptors
- cetuximab and panitumumab can beind to egfr
- w/ kras mutation, wont respond to anti EGFR
codon 12 and 13... should not receive the therapy |
|
|
Term
|
Definition
fusion gene : 9 22 in which tyrosine kinaes is always on.. cell dvision etc
CML = cancer in bone marrow (myeloid cells)
95% of pts w/ CML have BCR-ABL
Testing recommendation:
-Test CML pts only in advanced phase.
-During 1st line imatinib Tx if failure, resistance, or suboptimal response occurs. Mutations can occur over time based on TKI exposure
-During 2nd line dasatinib or nilotinib Tx w/ hematologic/cytogenetic failure. |
|
|
Term
|
Definition
1st gen TKI: targets ATP binding domain. displaces ATP
point mutations in P-loop A-loop and ATP binding and catalytic domain leads to resistance. [Mostly P-loop mutations]
Mechanisms of resistance:
-BCR-ABL amplification and over-expression
-acquisition of cytogenetic abnormalities by the leukemia clone
-expression of drug resistance proteins
-MOST COMMON: point mutations in ATP binding site/domain^^^^^ |
|
|
Term
Her2 and breast cancer
Trastuzumab |
|
Definition
Her2 = EGFR protein that the protooncogene ERBB2 codes for
- overexp in 30% of metastatic breast cancers
- no evidence that differs by race
Trastuzumab is a humanized monlconal antibody against Her2 that binds to inhibit dimerization/proliferative signals
HER + OK to use. if not then dont
test via FISH and immunohistochem (IHC)
TESTING IS REQUIRED prior to using trastuzumab |
|
|
Term
|
Definition
|
|
Term
|
Definition
use dasatinib
YEF359: DASA |
|
|
Term
| Serotonin Transporter Gene |
|
Definition
SLC6A4
-expression of gene may be altered by 44 BP insertion/deletion
-presence of insertion = long (L) allele = 2x gene expression
-absence of insertion = short (S) allele
- L allele present in 50-60% Caucasians and 30-40% Asians |
|
|
Term
| Variable number of tandem repeats (VNTR) w/in intron 2 of serotonin transporter (STin2) |
|
Definition
-small effect but still consistently associated w/ anti-depressant response
-may contain 9,10 or 12 copies of 16-17 BP repeat
(probably won't ask on test?) |
|
|
Term
| Serretti study: Meta-analysis of studies investigating L vs. S allele (serotonin) |
|
Definition
-increased remission rates w/ L/L and L/S genotype vs. S/S
-overall "response" not statistically significant
- 4 week response statistically significant w/ presence of L allele
-Caucasians: having L allele more relevant to reaching remission
-Asians: L allele did not seem as relevant to reaching remission |
|
|
Term
| Genome-Based Tx drugs for Depression (GENDEP) study: comparing escitalopram (SSRI) vs. nortriptyline (TCA) |
|
Definition
- results very predictable
-a few SNPs w/ relevant response in both tx groups exist in common antidepressant pathway
-significant SNP in serotonin gene more prevalent in escitalopram group
-significant SNP in norepinephrine gene more prevalent in nortriptyline group
-study predicted serum concentrations, but could not predict treatment response |
|
|
Term
|
Definition
CYP2D6 gene differences for CYP450 enzyme useful predictor for toxicity.
-amitriptyline = tertiary antidepressant
-nortriptyline = secondary antidepressant
-^both are hydroxylated by CYP2D6 (if inhibited you get accumulation of active drug)
-CYP2C19 genotype expression: effect escitalopram parent drug but not desmethylescitalopram (metabolite) levels. Effect both nortriptyline and 10-hydroxymortriptyline (metabolite) levels. |
|
|
Term
| CYP2D6 Population prevalence |
|
Definition
-Caucasians: 5-10% lack enzyme, *1, *3, *4, *5 and *6 most common alleles for red. metabolism. *3 and *4 allele 75% responsible for PM phenotype
-Asians: PM due to *10
-Africans: PM due to *17 |
|
|
Term
| PGx test for antidepressants |
|
Definition
-No FDA approved PG test for PD targets (aka how the drug will work) available from selected private labs, reimbursement unclear
-Several FDA-approved test for CYP2D6 and CYP2C19: despite availability tests don't get used, due to cost and lack of providers being able to interpret results, reimbursement not consistent
-Recommendation?: no evidence that testing is helpful or harmful according to EGAPP (evaluation of genomic applications in practice and prevention)
-Clinical recommendation: CYP2D6 and CYP2C19 genotyping may predict efficacy and toxicity. Testing prior to initiation of Tx not common. May not be necessary for low doses. |
|
|
Term
| CPIC Anti-depressant use recommendations based on genotyping data |
|
Definition
| -CYP2D6/CYP2C19 & TCAs: UM= avoid use or increase doe due to dec. efficacy, EM/IM (normal) = use recommended starting dose, PM = avoid use or lower dose 50% due to potential AEs |
|
|
Term
|
Definition
- Ideally provide report with recommendation for use of tx based on pt genotype
-Clinical studies folllowing utility of guided vs unguided Tx in psych outpatient setting: genetically guided = better outcomes |
|
|
Term
|
Definition
-Primarily metabolized by CYP3A4 to carbamazepine-10.11-epoxide. metabolite= major cause of hypersensitivity rxns (Steven-Johnson Syndrome/ Toxic Epidermal Necrolysis)
-low incidence of SJS/TEN rxns (<2 pt per million /yr), but mortality from rxns 5-35%
-high incidence for cutaneous drug rxn w/in 3 mo. of tx
-Genomic testing recommendation: FDA recommends test for HLA-B*1502 allele in Asian pts before starting carbamazepine or phenytoin.
-if pts have been treated previously long term, do not require testing |
|
|
Term
|
Definition
Gene/allele related to SJS/TEN rxns w/ carbamazepine use. No effect on clinical efficacy/dosing. Pts positive if 1 or 2 alleles of HLA-B*1502 present.
Mechanism: noncovalent interaction btwn drug and HLA-B*1502 complex --> CD8 Tcell mediated cell death
Race/Ethnicity Matters!
-Asians: 1-10% based on country of origin (study of 44 Han-Chinese showed 100% association)
-African: 0.2%
-European/Hispanic: 0%
-Caution w/ phenytoin, fosphenytoin, oxcarbazepine, and lamotrigine also! |
|
|
Term
|
Definition
GWAS showed cluster of 16 SNPs in CYP2C genes related to cutaneous ADRs
-CYP2C9*3 and phenytoin cutaneous rxns seen in asian populations
-CYP2C9*3 also associated w/ delayed clearance of plasma phenytoin
-CPIC Dosing recommendations (know this!)
-HLA-B*1502 carrier & CYP2C9 EM/IM/PM: if phenytoin naive, DO NOT USE
-HLA-B*1502 non-carrier & CYP2C9 EM: normal dose
-HLA-B*1502 non-carrier & CYP2C9 IM: start w/ 25% dose reduction
-HLA-B*1502 non-carrier & CYP2C9 PM: start w/ 50% dose reduction |
|
|
Term
|
Definition
-highly variable course of dz btwn pts
-phenotypic differences depending on dz "phase"
-no specific dz pathway elucidated
-Pharmacotherapy options cross multiple targets
-Lithium is gold standard tx, but only 1/3 patients are excellent responders. |
|
|
Term
| Requirements for Implementation of PGx into Practice |
|
Definition
-seamless integration into EMR
-PGx alerts (in EPIC for example)
-Integrated into medication orders and doses
-rapid turn around of test results
-storage of test results and ability to track easily (ideally in pt allergy section?)
-Consult service w/ clinical support
-incorporation into pt profiles for future monitoring
-education/ in-services for providers |
|
|
Term
| Potential Benefits to Providers |
|
Definition
-Explain or predict unexpected medication outcomes, such as elevated AEs, decreased efficacy, or tx failures
-ID pts at higher risk for certain medication interactions
-Reduce the need for sequential medication trials and prolonged symptoms
-Give an explanation or rationale for higher than expected doses needed to achieve efficacy
-Support a decision to continue or change the current
medication regimen |
|
|
Term
| Limitations of PGT (Pharmacogenetic) Testing |
|
Definition
Contribution to response from other patient
characteristics
– Age
– Lifestyle (diet, exercise, hydration)
– Treatment expectations
– Tolerance
– Adherence
• Drug interactions causing unexpected therapeutic
response
– PGT CAN help assess risk of interactions
• Disease state progression or interaction with
medication
• What the exact course of action will be!! |
|
|
Term
|
Definition
PGx: study of how genetic variation changes medications in general population
PGT: study of how variations change medications in INDIVIDUAL pt |
|
|
Term
| Altman paper: “Noninferiority sufficient” vs. RCTs |
|
Definition
1. Implementation of PGx is less challenging than general use of genomics for estimating disease risk and prognosis
2. Cost‐benefit analysis for PGx are not necessary before initial implementation; it is unlikely to lead to spiraling follow‐up test costs
3. The evidence base for initial clinical implementation of PGx is sufficient in many cases to propose noninferiority
4. PGx is well suited to adaptive and online comparative effectiveness research |
|
|
Term
| PGT Guidelines & Working groups |
|
Definition
-CPIC = Clinical Pharmacogenetics Implementation Consortium: peer reviewed guidelines, how to use genetic testing when it becomes available.
-DPWG = Dutch Pharmacogenetics Working Group: provide dosing recommendations based on PG data, goal to integrate into electronic systems
-CPMC = Coriell Personalized Medicine Collaborative: study how PG changes clinical practice |
|
|
Term
|
Definition
gene predictive of impaired folic acid metabolism into L-methylfolate. Can effect SSRIs/SNRIs. If biologically active effects NE, DA, 5Ht synthesis.
-50-60% of individuals have reduced or greatly reduced activity.
-SSRI tx w/ supplementation of L-methylfolate could improve response for those w/ reduced MTHFR activity |
|
|
Term
|
Definition
| use HSCT or ponatinib (3rd generation)... drug only approved for this use. |
|
|
Term
| A-loop mutation of TKI binding domain |
|
Definition
| will still likely respond to ALL TKIs |
|
|
