PK genetic variability Flashcards
name of study of link between genetic variability + reponse to treatment?
PG
PG used to individualise drug selection, give 2 examples
HER2+ cancer + Herceptin
ER+ breast cancer + Tamoxifen
Genetic polymorphism can impact the pharmacokinetics (PK) of drugs by affecting ADME.
name 3 gen polymorphism types?
enzyme
transporter
receptor
inUK Herceptin (trastuzumab) is licenced for what?
breast cancer spread beyond the breast
herceptin: antibody based treatment for which sub group of breast cancer px?
those with genetic mutation -> multiple copies of a gene that = overproduction of a tumour GF, HER2
what is HER2?
HER2 (human epidermal growth factor receptor 2)
overexpressed in some types of cancer, breast, ovarian, and gastric cancer. this -> uncontrolled cell growth and division, as well as resistance to chemotherapy and other treatments. Therefore, HER2 is an important target for cancer therapy.
2 Drugs that target HER2?
trastuzumab and pertuzumab
used to treat HER2-positive breast cancer.
what enzyme responsible for metabolism of 20% drugs, and polymorphism associated w differences in espression?
cyp2d6
4 types of cyp2d6 polymorphisms? results
complete deficiency
intermediate activity
extensive activity (normal px)
ultrarapid activity
what mutation -> ultrarpid activity of cyp2d6?
duplication of gene -> fast metab
more common in middle east and north africa
impact on PK will depend on whether cyp2d6 involved in…. 2
metab for ELIM (tricyclic antidepressants, antipsychotics)
metab for ACTIVATION (codeine -> morphine)
what enzyme converts prodrug codeine -> morphine for therapeutic effect?
cyp2d6
impact of px w decrease cyp2d6 on codeine -> morphine conversion?
little/ no conversion as poor metabolisers
will not experience pain relief but will become nauseated due to higher amounts of codeine in body
whats cyp2c9 responsible for?
metab of many NTIs…
- warfarin
- phenytoin
- losartan
- glipizide
- NSAIDs
polymorphism of cyp2c9 is linked to various abilities such as
WT 1/1 normal
other alloenzymes:
2/2: less metab activity
3/3: no activity
heterozygous genotypes: a mix 1/2 1/3 etc
t/f all other alloenzymes other than WT 1/1 of CYP2c9 are linked to reduced metab to some degree?
true
thus require dose adjustment: lower
why do you need lower dose for diff cyp2c9 metab?
low activity
high accumulation
lower dose to avoid tox
BUT consider therap window for NTI drugs
what drug metab in liver by CYP2C9, but a variant CYP2C9 gene alters rate of its metab?
warfarin
T/F
px with variant gene cyp2c9 break down warfarin slower so need lower doses to get same anticoagulant effect?
true
what can having too much anticoagulant eg high/normal dose warfarin in variant cyp2c9 gene px, lead to?
potentially dangerous bleesing and inc susceptibility to some drug ints
how is warfarin prescribed/ dosing?
start low
monitor blood clotting (INR)
increase slowly until approp lvl reached
whats CYP2C19 responsible for? metabolism of…
S-enantiomers of diazepam citalopram propanolol omeprazole
fluoxetine sertraline tricyclic antidepressants
3 types of results of cyp2c19 genetic polymorphism?
complete def
intermediate activ
extensive act: normal
there is a potentially higher efficacy of omeprazole, lansoprazole in X metabolisers of CYP2C19?
poor
higher risk of ADRs for X metab of CYP2C19 receiving warfarin and phenytoin
poor
T/F
lower activity of antimalarial drugs in poor metaboliser cyp2c19
(proguanil)
true
DDI + food (grapefruit) interactions seen with what enz?
cyp3A4
what does TPMT catalyse?
S-methylation of thiopurine rodrugs
eg azathiprine, mercaptopurine
polymorphism of TPMT observed in RBCs why?
enz in haematopoietic cells
TMPT ints: dose limiting.
whats low activity of enz linked to?
higher risk of haematological ADRs
requires phenotyping and dose adjustment
what does N-acetyltransferase (NAT) catalyse?
acetylation of diff drugs to allow elim
eg
isoniazid
hydralazine
phenelzine (MAOI)
NAT
for isoniazid (TB) what do slow acetylators need?
low doses to avoid neurological ADRs
NAT
for isoniazid (TB) what do fast acetylators have increased risk of?
hepatotoxicity (linked to metabolite conc)
for hydralazine (HTN) what do slow acetylators of NAT have increase risk of?
SLE-like syndrome
lupus like
what enz involved in glucoronidation of diff drugs?
UDP-glucoronosyltransferase
irinotecan: prodrug metab to SN-38, which is elim following what?
glucoronidation by UDP-glucoronosyltransferase
irinotecan can cause severe ADRs like
haematological and GI ADRs
diarrhea
sometimes fatal!
low UGT1A1 polymorphism associated w higher/ lower risk of ADRs?
higher
polymorphism of drugs transporters (ABC, solute) will impact on…
risk of disease
response to treatment
ADR risk
plasma concs
…
Pgp part of ATP binding treansport and..
resistance to therapy
Variability and special populations…
factors that can influence PK variability
genetics
age body size
disease
environemenatl
diet lifestyle
concomitant drugs (DDIs)
… adherence, pregnancy, alcohol, chronopharmacy (timing of drug admin)
2 types of Px variability: intra and inter- patient variability.
whats the difference?
intra: same dose same px
inter: same dose diff px
standard healthy subject =
75kg western male. clinical trials, not representative of whole popn
model not valid for:
paediatric
elderly
liver/ kidney disease
Hepatic and renal impairment…
diseases of what organs are responsible for large variations in drug PK?
organis of elim
also maybe circulatory system
what can diminished perfusion in HF affect in regards to PK parameters?
A: if affecting perfusion at absorption sites
D: assed quick in well perfused organs
M,E: if affect perfusion to liver +++ or kidneys.
depending on importance of hepatic metab and excretion for given drug
T/F: no single biomarker of hepatic disease?
true
severe cirrhosis decreases hepatic Cl but what other organs may it also affect?
intestine
lung
kidney
what PK parameter does liver disease mainly affect?
A
increase BA in cirrhosis
reduced FPM
worse for drugs heavily metab by liver
what classification system may be used for hepatic disease?
child-pugh classification
severe: 10-15
what PK parameters 3, can liver disease also affect?
D: decrease in protein lvls for protein unbound drugs
displacement/ comp w toxins
- changes in Vd for albumin bound drugs
- changes in Cl
M,E (bile)
CYP450 enz affected
how will a drugs BA and Cl change in disease state: cirrhosis?
increase
small decrease
what drugs should be used with caution in hepatic impairment and px monitored closely?
corticosteroids
… + NTI drugs always!
high extraction ratio (high liver metabolism) can experience inc/ dec in F?
inc (BA)
effect of hepatic flow reduced on renal Cl?
also reduced
how can oedema + ascite change Vd for hydrophilic drugs?
increase
as inc in total body water vol
for small drugs/ macromols in kidney disease, Cl reduced across the board?
small drugs
for macormols eg proteins, how does kidney disease affect Cl post metabolism?
reduced
but can distribute into interstitial space in inflamm/ cancer
in kidney disease are larger proteins mroe or less impacted and why?
less and glom filtration not major excretion route
reduced Cl -> what to t1/2
increases
- impact Css AND time to reach Css
- need dose reduction
kidney disease redcued protein binding so how is albumin conc changed?
decrease. and possible displacement
does kidney disease impact hepatic metabolism?
yes indirectly
uremic toxins can reduce hepatic enz activity
whats renal function measured in?
eGFR/ CrCl
GFR absolute =
eGFR x (BSA/1.73)
what is considered a suitable marker for renal func + is used for dosage adaptation?
CLcr
how much adjustment is needed for renal failure depends on what 2 things?
importance of renal excretion
severity of renal disease: larger dose change for more severe
Cl change will dpeend on drug, dialysis device properties, px.
more problematic for what type drugs?
hydrophilic, low PPB, small Vd
(As likely to be removed from body)
** also consider SA, membrane pore size **
why is kidney disease less of a problem for proteins + macromols?
similar size to albumin in blood- shouldnt be removed by dialysis
T/F
vancomycin is cleared at same rate as creatinine?
true
Special px populations….
why must anaesthetic drugs be considered in obesity?
they are highly lipid soluble thus accumulate in fatty tissue: lots in obesity
how is proportion of
- adipose tissue
- water
different in obesity?
and implications for polar drugs eg antipyrine
higher
lower
polar drugs will have lower Vd
3 parameters different in newborns which mean slower Abdorpiton of drugs in children?
low stomach acid levels
delayed gastric emptying
irregular inetstinal peristalsis
during first year of life, how does total body water as fraction of body wieght change?
decreases
but PPB also reduced
why does abilityof newborn to metabolise drugs differ quant and qual than older px?
as the avrious pathways of drug metab mature at diff rates
after the enzyme system matures at 6 months, what will metabolism depend on?
growth of liver
(perfusion, vol, bile function)
GFR normalised for BSA slowly increases and reaches adult values when?
about 6 months
in children, is drug Cl considered to correlate better with BSA or body weight?
BSA
thus higher maintenance dose per kg body weight needed the smaller and younger the child
what factors change with age/ in elderly that change drug distribution?
body fat increases
lean body weight decreases
so distribution of drugs sequestered into fatty tissues will be changed
T/F
changes to perfusion + cardiac output cannot also impact distribution rates
false they can
Vd of hydro/lipophilic drugs may be more effected in elderly?
lipophilic
how does liver mass and blood flow change with age?
decreases
so impacts on metab
why must adjustments be made for renally excreted drugs
glom filtration
kidney size
func glom
renal blood flow
all reduced
in pregnancy what 3 things can reduce absorption rates?
delayed gastric emptying
prolonged GI transit
reduced motility
… also elevated gastric pH and nausea, vom
preganncy linked w increased blood flow, decreased albumin and alpha-acid glycoprotein.
what will these affect?
protein binding.. more unbound drug
in pregnancy the inc lvls of unbound drug can affect response and increase risk of what?
ADRs
what in pregnancy can affect hydrophilic drug distribution?
increase in body weight linked to increase extracellular and intravascular volumes
what in pregnancy can affect lipophilic Vd?
increase in body fat
in pregnancy oestrogen and progesterone can cause what in metabolism?
induce and inhibit cyp metabolising enzymes
in preg, increase in blood flow can ->
lower plasma conc of drugs w high extraction ratio which will be metab more extensively
T/F in pregnancy, drugs with high extraction ratio will be metabolised more extensively
true
why does renal excretion of hydrophilic drugs increase in preg?
as renal blood flow increasea
why may some basic drugs become ionised (cross plasma exc in milk) + unable to transfer abck to plasma, in lactation?
as pH more acidic in breast tissue.
7.1
drugs are transported in breast milk by passive diffusion, so lipophilic may accumulate more/ less?
more
are macromols more/ less likley to be excreted in milk?
less
4 things that affect how much of drug is excreted in milk?
through plasma:milk conc grad?
dose
route
freq
time of feeding