TRANSPLANT 2 Flashcards
TACROLIMUS (1ST LINE)
CYCLOSPORINE (2 ND
LINE)
q
TACROLIMUS
indication
mech
Indication:
*Solid organ transplantation (kidney, liver, heart)
*Off-label for Crohn’s disease, graft-versus-host disease, rheumatoid arthritis.
*> 90% of current transplant recipients will receive tacrolimus (rather than
cyclosporine) – ELITE Symphony Study (Ekberg et al. N Engl J Med. 2007;
357:2562-2575): improved renal function, graft survival, reduced acute
rejection
*Mechanism:
*Binds to cytoplasmic immunophilins: FK-binding protein-12
*Tacrolimus-immunophilin complex inhibits calcineurin
*Blocks the activation/translocation of nuclear factor of activated Tcells (NFAT) → transcription/translation/production of IL-2
* T-cell activation and T-cell proliferation
TACROLIMUS
absorption
distribution
Absorption:
*Bioavailability highly variable (5-67%)
*Affected by intestinal/hepatic CYP3A4 and p-glycoprotein activities
*Food amount and rate of absorption (consistency is key to minimize
variation)
*Grapefruit juice CYP3A4 and p-glycoprotein → bioavailability
*Diarrhea absorption→ bioavailability
Distribution:
*Primarily into erythrocytes with typical blood:plasma ratio of ~35:1
*Use whole blood samples for therapeutic drug monitoring
*~76-99% protein bound to albumin and alpha-1-acid glycoprotein
So the higher the expression of CYP3A4 the lower the concentration of tacro
avoid grateful Jups way through products because they inhibit, sip 3 a 4,
and keep pgp, and therefore can increase drastically. Increase the concentration
Whenever the patient has diarrhea from any others for any others, and any source they’re capable of. This concentration will shoot up drastically. Exact mechanism not known
MPA we monitored plasma
For tacro we monitor whole blood because it distributes into blood cells
it is also highly protein bound. So, therefore.
because it is primarily given orally, it’s going to behave like a low E drug. It’s going to be affected by protein binding displacement interactions.
TACROLIMUS
*Metabolism and Excretion
Extensively metabolized by intestinal/hepatic CYP3A4/5 and
transported by p-glycoprotein→ drug / gene interactions
* Primarily fecal elimination
*Clearance: 0.04 – 0.08 L/h/kg
*Half-life: 2.3-36 hours (avg ~ 12 hrs, how many days to steady-state?)
TACROLIMUS
Adverse effects:Concentration dependent:
*Concentration dependent:
*Nephrotoxicity
*reversible, incease serum creatinine, blood urea nitrogen, K+
*Mitigation: delayed dosing of calcineurin inhibitors;
dose adjustment; avoidance of other nephrotoxic drugs
(aminoglycosides, NSAIDs, vancomycin)
*Mechanism: afferent arteriole renal vasoconstriction →
30% decrease in eGFR
ACE inhibitors has same mechanism?
There is not contraindication for using ACEi, but because they also have the same side effects to nephrotoxicity. The you may. You may not want to start them at the same time.
TACROLIMUS
*Adverse effects:
*Concentration dependent:
other
- Neurotoxicity (hand tremors, headache, peripheral neuropathy) [more likely than
cyclosporine] - Dermatologic (alopecia – reversible) [cyclosporine causes hirsutism]
- Gastrointestinal (diarrhea)
- Infections
- Post-transplant diabetes [more likely than cyclosporine]
- dose-dependency?
- Mechanism: direct toxic effects on pancreatic islet cells?
- Incidence higher in obese patients, African Americans, Hispanics, prior history of diabetes
- Monitor drug-drug interactions (e.g., steroids)
- Hyperkalemia (monitor drug-drug interactions: ACE-I, potassium sparing diuretics such as
amiloride, spironolactone, eplerenone, triamterene) - Hypomagnesemia
TACROLIMUS
*Adverse effects:
*Non-concentration dependent:
*Anaphylaxis and allergic reactions due to castor oil derivative in the IV
formulation
*Cardiac hypertrophy (rare)
TACROLIMUS
*Drug-Drug interactions:
*Clinically relevant pharmacokinetic interactions that exposure
(via CYP3A4 & p-glycoprotein inhibition):
*Azole antifungals (fluconazole, voriconazole…etc)
*Macrolide antibiotics (erythromycin, clarithromycin)
*Fluoroquinolones (levofloxacin, ofloxacin)
*Non-dihydropyridine calcium channel blockers (verapamil, diltiazem)
*Antidepressants: nefazodone
*Clinically relevant pharmacokinetic interactions that exposure
(via CYP3A4 & p-glycoprotein induction):
*Antibiotics (Rifampin)
*Anti-seizures (carbamazepine, phenytoin, phenobarbital)
TACROLIMUS
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Drugs that can cause immunosuppression, nephrotoxicity, CNS toxicities
TACROLIMUS
*Therapeutic drug monitoring
*Trough concentration in whole blood (usually 5 – 20 ng/mL); target based on
indication and time post-transplant. Target typically higher immediately posttransplant and gradually reduced over 3-4 months.
* Rate of concentration target change dependent on patient’s clinical status.
*Limited sampling strategies (Rarely used. For AUC estimation, but lacking targets)
*Trough concentration “variability” with better prediction of efficacy and toxicity
(Rarely used today)
*Dried blood spotting (interests from clinicians and pharmaceutical scientists)
*Note: concentrations obtained from different analytical assays are not
interchangeable. Immune assays usually report higher concentrations (crossreactivity). Target ranges tailored to each specific assay.
TACROLIMUS - PHARMACOGENOMICS
if you carry copies of functional, c. 3 a 5. You’re going to metabolize top of them as faster
than the other patients who does not carry
functional copies
That will lead to reduftion in blood conc of tac
you have to increase the dose to compensate for this effect. Does that make sense? Yeah. So this this is a strong recommendation.
So this is why they recommend extensive metabolizers. You’re going to have significantly reduced concentration, blood concentration, tackle limits. You’re going to have to use the higher dose as a starting dose
genomics, remember, only helps with starting a therapy. It doesn’t help with a patient was already stabilized
right? So this will help you pick a starting dose.
but because you’re going to have to monitor the concentration. Anyways
you will eventually arrive at the right dose. So what it does is it? It possibly makes it faster for you to reach
good dose
Intermediate metabolizer also increases, starting those as well based on strong evidence.
poor metabolizer use the normal dosage
TACROLIMUS - PHARMACOGENOMICS
contd
Kiang: “CYP3A5 expression status can help improve concentration target attainment; however, the
effects of genomic doing on actual clinical outcomes (i.e. graft rejection, adverse effects) are not yet
known.” – recent CSHP BC branch talk on pharmacogenomics
CF is a 55-year-old man who just received a liver transplant.
His current immunosuppressive regimen is IV
methylprednisolone 160mg/day and mycophenolate mofetil
1,000mg PO BID. His weight is 80kg and his serum creatinine is
85 µmol/L (N=60-110). The liver donor had previously been
determined to have the CYP3A51/1 (wild-type) genotype.
What dose (immediate release or extended release) of
tacrolimus would you use?
Recommended tacrolimus (immediate release) dose is 0.1-0.15
mg/kg/day. Team decides to use 0.14 mg/kg/day given as
0.07 mg/kg every 12 hours
Immediate release formulation usually started first in hospital
(more flexibility for dose adjustment)
Daily dose = 80kg x 0.14 mg/kg/day = 11 mg/day,
administered 5.5 mg PO Q12h
If no genetic data available, start at lower doses (than
calculated maintenance dose – why?) and gradually increase
over next few days to target dose
Or, start at target dose and measure level at steady-state
(how many days?)
If renal function does not recover, may consider holding
tacrolimus
If genetic info available, follow CPIC (Clinical
Pharmacogenetics Implementation Consortium) guideline:
↑ maintenance dose: 8 - 9 mg PO BID
Monitor tacrolimus trough concentrations (when would you
monitor?)
Average/median typical half life = ~12 hrs, draw level in 2-
3 days
CF continues to improve clinically 4 days after the liver
transplant. Owing to his CYP3A51/1 genotype, the team
had started him on a higher tacrolimus dose of 9 mg PO BID
(on day 1 post-transplant). Trough tacrolimus concentrations
have been obtained serially in the morning on day 2 (6.3
ng/mL), day 3 (7.5 ng/mL), and day 4 (8 ng/mL). The team
would like you to adjust the tacrolimus dose to achieve a
trough concentration of 12 ng/mL. Please show your approach.
PK of tacrolimus is highly variable.
Linear proportionality between dose and exposure is usually
assumed in the clinic
Assuming nothing else has changed (renal function, liver
function, co-administered drugs), use the following to estimate
new dose:
Desired dose = desired conc / current conc * current dose
Desired dose = 12 / 8 * 9 = 13.5 mg, given BID
Recheck trough concentrations in 2 – 3 days
LJ is a 45-year-old woman who had a liver transplant. She is
receiving a stable regimen of tacrolimus 8mg PO BID and
prednisone 5mg PO daily. Two weeks ago, her tacrolimus
concentration was 6 ng/mL. She was prescribed diltiazem XR
300mg PO daily for hypertension 1 week ago, and now
presents with headaches and tremors. Her serum creatinine is
120 µmol/L (baseline is 85 µmol/L, Normal=45-90), and her
tacrolimus concentration is now 9 ng/mL (her specific target is
4-6 ng/mL). How can you account for the elevated tacrolimus
concentration? How would you manage her tacrolimus dose to
achieve a tacrolimus concentration of 4-6 ng/mL?
Adverse effects (nephrotoxicity & neurotoxicity) likely secondary
to tacrolimus
Make sure level is drawn at appropriate time relative to last dose
given – “trough” target
Any other medications or food that can interact with tacrolimus?
Tacrolimus is a substrate of CYP3A4/5 and p-glycoprotein
Diltiazem is an inhibitor of CYP3A4/5 and p-glycoprotein:
increased absorption and decreased metabolism
Option 1: use an alternative anti-hypertensive agent (which ones?)
Option 2: decrease dose of tacrolimus to 5mg PO BID (based on
concentration-dose proportionality)
MJ is a 55-year-old male who received a kidney transplant 3
months ago. He presents with a 2-day history of cough and
fever. A chest radiograph reveals a lesion consistent with
pulmonary aspergillosis. MJ is started on antifungal therapy
with IV micafungin (100mg IV daily). After 1 week of therapy,
MJ has responded well to IV therapy and is to be transitioned
to oral voriconazole. His immunosuppression regimen consists of
tacrolimus 6 mg PO BID, prednisone 5 mg PO daily, and
enteric coated mycophenolic acid 720 mg PO BID. The most
recent tacrolimus concentration was 6 ng/mL. Are there any
dosage modifications to MJ’s immunosuppressive regimen that
should be considered prior to starting voriconazole? How
should tacrolimus concentrations be monitored?
Voriconazole is a potent inhibitor of CYP3A4 and pglycoprotein and can ↑ tacrolimus exposure by ~ 3 fold
(clinical data)
Decrease tacrolimus dose to 1/3 to minimize the interaction
Monitor tacrolimus concentrations once BOTH tacrolimus and
voriconazole (half-life ~ 6 hours) have reached steady-state.
Monitor graft function
PS is a 57-year-old male who received a kidney transplant 3
months ago. He reports decreased urine output and gaining ~
10kg over the past week. His creatinine is now 130 µmol/L
(N=60-110). His creatinine was 80 µmol/L 3 weeks ago. His
immunosuppression regimen consists of tacrolimus 6mg PO BID
and prednisone 5mg PO daily. Other medications include
metoprolol 25mg PO BID, dapsone 100mg PO daily,
gliclazide 40mg PO BID, and naproxen 500mg PO BID as
needed for knee pain (started about 2 weeks ago). How
would you assess PS’s renal function?
Kidney rejection & calcineurin toxicity can have similar
presentations (increased serum creatinine, weight gain, decreased
urine output → acute rejection)
Obtain a tacrolimus concentration
Conduct kidney ultrasound and biopsy to rule out acute rejection
Assess compliance
Assess transplant meds: why not on MMF/azathioprine/sirolimus?
Assess non-transplant meds: are there other nephrotoxic drugs?
Switch naproxen to another analgesic
CYCLOSPORINE
indication mech
*Indication:
*Solid organ transplantation (kidney, liver, heart)
*Off-label for rheumatoid arthritis, psoriasis, and nephrotic syndrome
*Considered 2nd line therapy vs. tacrolimus (different pattern of toxicity
and reduced efficacy) – Liu et al. Am J Ther. 2016;23:e810-824.
*Mechanism:
*Binds to cytoplasmic immunophilins: cyclophilin
*cyclosporine-cyclophilin complex inhibits calcineurin
*Blocks the activation/translocation of nuclear factor of activated Tcells (NFAT) → transcription/translation/production of IL-2
* T-cell activation and T-cell proliferation
CYCLOSPORINE
Absorption:
distribution
Absorption:
*Bioavailability highly variable (Sandimmune: 20-50% vs. Neoral: mean
30%, up to 60% observed)
*Tmax ~1.5-2 hr (Neoral)
*Food Cmax by ~33% and AUC by ~13% (Neoral)
*Metabolized by CYP3A4 and p-glycoprotein (grapefruit juice absorption)
Distribution:
*Distributes outside of the vascular compartment (Vd ~ 4-6 L/kg;
comparatively much larger than tacrolimus which primarily stays in the
vasculature)
*Highly protein bound (~90% to lipoproteins)
*Can distribute into the placenta and breast milk
Appropriate for use in preg and lac
CYCLOSPORINE
*Metabolism and Excretion
*Extensively metabolized by intestinal/hepatic CYP3A4/5 and
transported by p-glycoprotein→ drug / gene interactions
*> 25 metabolites identified to date (all inactive)
*Primarily by biliary / fecal elimination
*Half-life: 5-18 hours (how many days to steady-state?)
so similar to tackle them. Is it will take a couple of days to reach steady state, so we we don’t draw the level right away after changing the dose.
CYCLOSPORINE
*Adverse effects:
*Concentration dependent
*Nephrotoxicity
*Incidence / severity / mechanism similar to tacrolimus
*Neurotoxicity (hand tremors, headache, peripheral neuropathy)
[less likely than tacrolimus]
*Hypertension and hyperlipidemia [much more likely than
tacrolimus]. ~50% incidence of hypertension.
*Dermatologic (hirsutism) [tacrolimus causes alopecia]
*Gingival hyperplasia [not observed with tacrolimus]
*Hyperkalemia
*Hypomagnesemia
*Hepatotoxicity ( transaminases)
you’re gonna start with diet regiments exercise. But eventually
we’ll need to consider the formal therapy for hyperlipidemia
- Many ppl on statins post tansplant
Dilantin, phenytoin causes gingival hyperplasia
recommendation dental hygiene well sometimes will help
CYCLOSPORINE
*Adverse effects:
Non-concentration dependent:
*Allergic reactions due to cremophor derivative in the IV formulation
CYCLOSPORINE
*Drug-Drug interactions:
*Exceptions:
Drug-Drug interactions:
*Clinically relevant pharmacokinetic interactions:
*Essentially the same as tacrolimus (via CYP3A4 and p-glycoprotein)
*Exceptions:
*Cyclosporine inhibits enterohepatic recirculation of mycophenolate and
MPA clearance [tacrolimus does not exhibit this effect]
*Dose-adjustment (i.e., higher MPA dose) required when MPA given concurrently
with cyclosporine vs. with tacrolimus
*Cyclosporine can inhibit CYP3A4, p-glycoprotein, organic anion
transporter proteins (e.g., statins metabolized by CYP3A4→
rhabdomyolysis)
Increases statin conc - use rosuvastatin to avoid the interaction (PGP)
CYCLOSPORINE
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Drugs that can cause immunosuppression, nephrotoxicity, hypertension,
dyslipidemia
