Transplant Flashcards
what are the 2 categories of graft rejection
acute cellular
humoral/ chronic
describe acute cellular graft rejection
infiltration of T cells into allograft = inflam + cytotoxic effects
describe humoral/ chronic graft rejection
cellular cytokines, CD4+ and CD8+ T cells, B cells, antibodies
what are the 3 steps of the T cell activation process
T cell identifies antigen bound to MHC
Costimulatory signal needed for T cell activation (CD80/86- CD28 interaction)
Increased IL2 generation, feedback amplification
3 main targets of transplant pharmacotherapy
Optimize ABO blood type + HLA match (organ donation team, Canadian Blood Services)
Combinatorial pharmacotherapy:
- Induction: short duration, max immunosuppression, peritransplant
- Maintenance therapy
Maintaining fine balance between drug efficacy and toxicity in the setting of multiple comorbidities (CV, endocrine, bone mineral, infectious disease)
AZA and MPA are part of the ________ class and work by ____________
antimetabolites
inhibiting purine synthesis and T cell proliferation
cyclosporin and tacrolimus are part of the ________ class and work by _______
calcineurin inhibitors
reducing IL2 and T cell activation
sirolimus is part of the _____ class and works by ________
mTOR
decreasing IL2 production
MPA’s primary indication is
solid organ transplant (kidney, lung, heart, liver)
why did MPA replace AZA as anchor drug
increased efficacy, pt and graft survival
MPA MOA (3)
Noncompetitive binding to inosine monophosphate dehydrogenase (IMPDH - type 2 (lymphocyte specific) = ↓ off target toxicity)
Blocks guanosine nucleotide synthesis, ↓ DNA polymerase activities
↓ T and B cell proliferations
MPA IV is not preferred because
will have to switch to PO anyways
max 14 days IV use only if not tolerating IV
what is the dose limit of MPA in pts with severe kidney impairment
2g/d
people who develop _________ may require a decrease in MPA dose
neutropenia
what is the conventional starting dose of MPA
1g PO BID MMF
T or F: typically a LD of MPA is delivered
F
T or F: MMF and EC-MPS are not interchangeable due to differences in metabolism and distribution
F- not interchangeable due to differences in absorption
what is the effect of food on MMF and EC-MPS
decreases Cmax by 30-40% but AUC stays the same
consistency is key
MPA distribution characteristics (into what? bound? placenta? lactation?)
primarily into plasma
extensively bound to albumin
may distribute into fetus and milk = CI in pregnancy = switch to AZA
T or F: MMF is a prodrug
T
MPAG is excreted into bile by
MRP2
MPAG is deconjugated in intestines by bacteria and ___________
recycled back into systemic circulation by enterohepatic recirculation
MPAG is excreted ________ by ____ and ____
renally
PAT3 and MRP2
3 SEs of MPA
Gi upset
hematological- neutropenia, leukopenia, anemia
infections
what can you do about MPA GI upset
switch MMT to EC-MPS or split dose into QID with food or snack
what can you do about MPA neutropenia
empirically decrease dose by 25-50% + monitor pt for CBC, renal fxn, sx infxn, sx rejection
what drugs increase MPA AUC? how?
acyclovir- decreases renal excretion
what drugs decrease MPA AUC? how
↓ AUC: Al/Mg containing antacids (abs), cholestyramine (abs), PPIs (abs), cyclosporin (enterohepatic recirc), antibiotics
what types of drugs cause PD intx with MPA
Drugs that can cause immunosuppression/ leukopenia/ neutropenia
is TDM practiced with MPA?
no unless active rejection, evidence of AEs, abnormal kinetics
how is TDM of MPA done?
limited sampling strategy
what is the therapeutic target of MPA
AUC 30-60mgh/L
AZA indication
kidney transplant and RA
what is the 2nd line antimetabolite in transplant
AZA
AZA is a ______
prodrug
describe AZA metabolism
AZA to 6MP to 6 thioguanine nucleotide (halts lymphocyte DNA replication)
AZA is deactivated by (3)
xanthine oxidase, TPMT, NUDT 15
describe AZA absorption characteristics
F 40%
effects of food not well characterized = just be consistent
describe AZA distribution
6-MP distributes into today body water = ~ Vd
not extensively protein bound
distributes into placenta
what converts AZA to 6-MP
hepatic glutathione S-transferase
what converts 6-MP to 6-TGN
hypoxanthine guanine phosphoribosyltransferase
what deactivates 6-MP
xanthine oxidase and TPMT
what 2 drugs inhibit xanthine oxidase, causing an increase in 6MP?
allopurinol and feboxustat
TGN is deactivated by
NUDT15
AZA metabolites are ________ excreted
renally
AEs of AZA
GI
hematological (can occur within wks - typically manage with dose reduction) + (correlated with reduced TPMT and NUDT15 activities or concurrent xanthine oxidase inhibitors)
dose dependent liver toxicity (cholestatic and hepatocellular)
alopecia, pancreatitis (Rare)
hematological AEs from AZA are typically due to
reduced TPMT and NUDT15
xanthine oxidase inhibitors
2 drug gene intx with AZA
TPMT
NUDT15
what happens with AZA and xanthine oxidase inhibitors
XO increases 6-MP conc by up to 4x = shunts metabolism to increase 6-TGN production = bone marrow suppression
is TDM commonly done for AZA?
no
tacrolimus indication
SOT (kidney, liver, heart)
why is tacro preferred to cyclo
improved renal function, graft survival, reduced acute rejection
MOA tacrolimus
binds to cytoplasmic immunophilins FK binding protein 12
tacrolimus immunophilin complex inhibits calcineurin
blocks activation/ translocation of NFAT = decr transcription/ translation/ production of IL2
decr T cell activation and proliferation
describe tacrolimus absorption characteristics
bioavailability highly variable
affected by intestinal/ hepatic CYP3A4 and P-gp activities
food decreases amt and rate of absorption
grapefruit juice dec 3A4 and P-gp = incr bioavailability
diarrhea = incr abs = incr bioavailability
what is the effect of grapefruit juice and diarrhea on tacro absorption
grapefruit juice dec 3A4 and P-gp = incr bioavailability
diarrhea = incr abs = incr bioavailability
tacrolimus primarily distributes into
erythrocytes
for tacrolimus TDM, a _____ should be used
whole blood sample
76-99% of tacro is protein bound to ___ and _____
albumin
alpha-1-acid glycoprotein
tacrolimus is eliminated
fecally
what is a major conc dependent AE of tacro
nephrotoxicity- reversible, incr SCr, BUN, K+
how to mitigate tacro nephrotoxicity
delayed dosing of CI, dose adjust, avoid other nephrotoxic drugs (aminoglycosides, NSAIDs, vanco)
what is the mech of tacrolimus induced nephrotoxicity
afferent arteriole renal vasoconstriction = 30% decrease in eGFR
list 4 sx of acute kidney rejection
fever, <4wks post op, weight gain, graft tenderness/ swelling, decreased daily urine volume, rapid rise in SCr, normal CSA or TAC concs, interstitial lymphocytic infiltrates
list 4 sx of CSA or TAC nephrotoxicity
> 6wks post up, no fever, nontender graft, good urine output, gradual rise in SCr, elevated CSA or TAC, interstitial fibrosis, tubular atrophy, glomerular thrombosis, arterial inflam
list 3 other sx of TAC AEs conc dependent
Neurotoxicity: hand tremors, HA, peripheral neuropathy
More likely than cyclosporine
Dermatologic: alopecia (rev)
cyclo causes hirsutism
GI: diarrhea, Infections
Post transplant DM
More likely than cyclosporin
MOA: direct toxic effects on pancreatic islet cells
↑ in obese pts, African Americans, Hispanics, prior hx HM
Monitor DDI (steroids, HCTZ, etc = ↑ risk)
Hyperkalemia
Monitor DDI; ACEi, K sparing diuretics like amiloride, spironolactone, eplerenone, triamterene
Hypomagnesemia: v common with IV
Take Mg = diarrhea = ↑ tac conc = caution
post transplant DM is more common in (cyclo or tacro)
tacrolimus
hypomagnesia with tacrolimus is more common with
IV
what is a caution in tx tacro induced hypomagnesia
Mg = diarrhea = increased tac conc = AEs
what drugs increase tacro exposure
azole antifungals
macrolide antibiotics
fluoroquinolones
NDHP-CCBs
antidepressants
what drugs decrease tacro exposure
antibiotics (rifampin)
antiseizure meds (carbamazepine, phenytoin, phenobarbital)
what is the pref antiseizure med if pt is using tacro
levetiracetam
what is the preferred antihypertensive if the pt is using tacro
amlodipine
tacro has PD intx with drugs that cause
immunosuppression, nephrotoxicity, CNS toxicities
is TDM commonly used with tacrolimus
sometimes to monitor SS at 2-3 days
list the 4 ways of tacro TDM
trough conc in whole blood
limited sampling strategies
trough conc variability
dried blood spot testing
the target in trough conc testing in whole blood for tacro is
5-20ng/mL- but based on indication and time post transplant
target typically higher immediately post transplant + gradually reduced over 3-4mths
how often is limited sampling strategies of tacro used
rarely
T or F: different analytical assays for tacro are interchangeable
F- not interchangeable
immune assays may report higher conc due to cross reactivity
target ranges are tailored to each specific assay
how does PGX play a role in using tacro
only for initiating doses, not for maintenance
how should tacro dose be adjusted for EM or IM
increase starting dose by 1.5-2x starting dose
how should tacro dose be adjusted for PM
initiate tx with standard rec dose
cyclosporin indication
solid organ transplant (kidney, liver, heart)
2nd line comp tacro
cyclosporin MOA
binds to cycophilin
cyclosporin-cyclophilin complex inhibits calcineurin
blocks activation/ translocation of NFAT = decreased transcription/ translocation/ production of IL2
= decr T cell activation and proliferation
what are the 2 cyclosporin formulations
original- variable + incomplete GI absorption, v large interindividual variability- not commonly used
modified- microemulsion with improved bioavailability
are the original and modified formulations of cyclosporin interchangeable?
no
describe cyclosporin bioavailability and absorption
bioavail highly variable
food decreases Cmax by 33$ and AUC by 13$
cyclosporin is metabolized by ___________ and has _______ (active/ inactive) metabolites
CYP3A4 and P-gp
>25 inactive metabolites
describe cyclosporin distribution
distributes outside of vascular compartment (much larger than tacro which stays in vasculature)
highly protein bound (90% to lipoproteins)
can distribute into placenta and breast milk
cyclosporin is highly ____ bound
lipoprotein
cyclosporin is mainly _____ eliminated
biliary/ fecal
list 3 conc dep AEs of tacro
nephrotoxicity
neurotoxicity
HPTN and hyperlipidemia
dermatological
gingival hyperplasia
hyperkalemia
hypomagnesemia
hepatotoxicity
which of the following AEs are more likely with tacrolimus? (select all that apply)
1. nephrotoxicity
2. neurotoxicity
3. HPTN
4. hyperlipidemia
5. gingival hyperplasma
2
allergic reactions to cyclosporin are likely due to
cremophor derivative in IV formulation
how does cyclosporin impact mycophenolate and MPA CL
inhibits enterohepatic recirculation- dose adjustment needed when MPA given with cyclo (not an issue with tacro)
cyclosporin can inhibit ___, ____, ____
CYP3A4, P-gp, OAT
what is the interaction between statins and cyclosporin
cyclosporin inhibits CYP3A4 = more [statin] if metabolized by 3A4 = rhabdo = use rosuvastatin to avoid intx
there are clinically relevant PD interactions with tacro and drugs that cause (4)
immunosuppression, nephrotoxicity, HPTN, dyslipidemia
how is cyclosporin TDM done
trough conc in whole blood
C2 level
limited sampling strategies
what is the target for trough conc in whole blood of cyclosporin
75-450mcg/L or ng/mL
target typically higher immediately post transplant + gradually reduced over 3-4mths
which of the following is more accurate for estimating exposure to cyclosporin
1. trough conc in whole blood
2. C2 level
3. limited sampling strategy
2
describe the use of pharmacogenomics with cyclosporin
no evidence to use it yet
the oral dose of cyclosporin should be ____ parenteral dose
3x
there is a higher risk of rejection within ____ post transplant
1mth
what is the primary indication for sirolimus
kidney transplant (but also for liver and heart)
T or F: sirolimus is 1st line tx in transplant combo tx
F
sirolimus is used in pts ___________________________
intolerant to CI (nephrotoxicity) or those with evident skin cancer
sirolimus is used in combo with
lower dose CI (+ prednisone) or calcineurin inhibitor free regimens (+MOA and prednisone)
sirolimus is only started after ___________ due to ___________
> 3 mths post transplant
delayed wound healing effects (typically not used in de novo pts)
what is sirolimus MOA
binds to FKBP12, but complex doesn’t inhibit calcineurin activity
sirolimus-FKBP12 inhibits mTOR (a protein kinase responsible for G1 to S cell cycle progression) = stops cell division = decr T cell proliferation + anticancer effects
is a LD required for sirolimus
maybe- some centers will just overlap immuosuppressants
are tablet and solution sirolimus interchangeable
no- but the 2mg dose is roughly eq between the 2 doses
describe sirolimus absorption
F ~15%
fatty foods decrease Cmax by 30% (consistency is key)
grapefruit juice decreases CYP 3A4 and P-gp = higher bioavailability
describe sirolimus distribution
blood:plasma ration 37:1- use whole blood for TDM
~92% bound to albumin
can sirolimus be used in pregnancy
no
sirolimus is extensively metabolized by ___________ and transported by _____
intestinal/ hepatic CYP3A4/ 5 and transported by P=gp
sirolimus undergoes primarily _____ elimination
fecal
in pts with liver dysfxn, sirolimus dose should be decreased by ___
1/3
is a LD required for sirolimus?
yes- due to time it takes to reach SS (half life is 62hrs)
list 3 SEs of sirolimus
↑ neurotoxicity associated with CI
Myelosuppression = thrombocytopenia, leukopenia, anemia (may be transient), observed within 1st weeks of initiating drug)
hypercholesterolemia/ hypertriglyceridemia (may req pharmtx, obs within first few mths)
↑ lipoproteins + ↓ lipoprotein lipase
GI toxicities/ mouth ulcers (up to 60% pts)
Lymphocele: lymph fluid drains out + accum in cavities
Hypokalemia
Delayed wound healing/ hepatic artery thrombosis
Avoid immediately post surgery/ liver operations
nonconc dep: anaphylaxis, dermatitis, angioedema, vasculitis, interstitial lung disease, arthralgia
_____ increases sirolimus Cmax and AUC (and vice versa)
cyclosporin
if you must give cyclosporin and sirolimus, how should they be dosed
separate admin by 4 hrs
what are 3 clinically relevant DDIs for sirolimus
myelosuppression, hypercholesterolemia, hypertriglyceridemia
what is everolimus used for
similar indication as sirolius + also used in liver transplant pts
which has more SEs on wound healing- sirolimus or everolimus?
sirolimus
which has less SEs regarding neurotoxicity with tacro or cyclo- sirolimus or everolimus
everolimus
prednisone indication
Solid organ transplant (kidney, liver, heart, lung) and many other inflammatory conditions
Prednisone primarily used in transplant (others include prednisolone, methylprednisone)
prednisone MOA
multiple targets with decrease in translocation/ fxn of proinflammatory transcription factors = decreased cytokine production = decreased overall inflammation
what is the steroid avoidance type of prednisone dosing
only methylprednisolone peritransplant (for low immunologic risk)
what is rapid steroid withdrawal dosing of prednisone
prednisone withdrawal quickly post transplant over 7 days (for low immunological risk
what is early steroid withdrawal type of steroid dosing
prednisone withdrawal over first few months post transplant (low imm risk)
withdrawal of prednisone can increase risk of acute rejection but __________
may not affect LT outcomes in select pst
what is the low dose steroid maintenance
prednisone never withdrawn, but tapered to lowest maintenance dose possible
what is the most common type of prednisone dosing
low dose steroid maintenance- admin in am to mimic body’s diurnal release of cortisol
how is prednisone’s bioavailability
90%, well absorbed
food effect no well characterized- may increase T max- can take with food to decrease GI upset
prednisone requires bioactivation to
perdnisolone
prednisone has _____ kinetics and ______ with large doses
nonlinear
increased Vd with large doses
T or F: prednisone can’t distribute into placenta and breastmilk
F- can
prednisone has saturable binding to ____ and _____
albumin and transcortin
how is prednisone metabolized
phase 1 and 2
how is prednisone excreted
renally
is TDM commonly done on prednisone? why or why not
not commonly done due to wide therapeutic range
is PGX relevant to prednisone dosing?
no- insuff evidence
ist 3 prednisone AEs
CNS toxicity: nightmares, psychosis, depression
Ocular: IOP, glaucoma, cataract
Adrenal suppression: ↓ HPA axis =
20adrenal insuff = req stress dosing for surgery, infxn, trauma
Cushingoid appearance: truncal obesity, facial adipose tissue (moon face), dorsocervical adipose tissue, striae, acne, hirsutism
CV: HPTN, dyslipidemia, fluid retention, ↓K+, ↑Na+, arrhythmias (intx with cyclosporin, mTOR inhibitors)
Endocrine: hyperglycemia (intx w/ tacrolimus and antidiabetics)
Neuromuscular and skeletal: osteoporosis, bone fractures, myopathy, osteonecrosis
GI: PUD, gastritis, esophagitis
Infxns: viral, bacterial, opportunistic (causes leukocytosis)
↓ growth rate in children
prednisone interacts with _______ and _______
CYP3A4 and P-gp
prednisone can potentially induce phase ___enzymes- this results in ___________________ for other transplant drugs
1+2 = increased CL of tacrolimus, cyclosporin, sirolimus, mycophenolate
