TRANSPLANT 2

Question 1

TACROLIMUS (1ST LINE)
CYCLOSPORINE (2 ND
LINE)

Answer 1

q

Question 2

TACROLIMUS
indication
mech

Answer 2

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

Question 3

TACROLIMUS
absorption
distribution

Answer 3

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.

Question 4

TACROLIMUS
*Metabolism and Excretion

Answer 4

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?)

Question 5

TACROLIMUS
Adverse effects:Concentration dependent:

Answer 5

*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.

Question 6

TACROLIMUS
*Adverse effects:
*Concentration dependent:
other

Answer 6

• 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

Question 7

TACROLIMUS
*Adverse effects:
*Non-concentration dependent:

Answer 7

*Anaphylaxis and allergic reactions due to castor oil derivative in the IV
formulation
*Cardiac hypertrophy (rare)

Question 8

TACROLIMUS
*Drug-Drug interactions:

Answer 8

*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)

Question 9

TACROLIMUS
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:

Answer 9

*Drugs that can cause immunosuppression, nephrotoxicity, CNS toxicities

Question 10

TACROLIMUS
*Therapeutic drug monitoring

Answer 10

*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.

Question 11

TACROLIMUS - PHARMACOGENOMICS

Answer 11

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

Question 12

TACROLIMUS - PHARMACOGENOMICS
contd

Answer 12

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

Question 13

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?

Answer 13

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

Question 14

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.

Answer 14

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

Question 15

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?

Answer 15

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)

Question 16

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?

Answer 16

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

Question 17

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?

Answer 17

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

Question 18

CYCLOSPORINE
indication mech

Answer 18

*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

Question 19

CYCLOSPORINE
Absorption:
distribution

Answer 19

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

Question 20

CYCLOSPORINE
*Metabolism and Excretion

Answer 20

*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.

Question 21

CYCLOSPORINE
*Adverse effects:
*Concentration dependent

Answer 21

*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

Question 22

CYCLOSPORINE
*Adverse effects:

Answer 22

Non-concentration dependent:
*Allergic reactions due to cremophor derivative in the IV formulation

Question 23

CYCLOSPORINE
*Drug-Drug interactions:
*Exceptions:

Answer 23

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)

Question 24

CYCLOSPORINE
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:

Answer 24

*Drugs that can cause immunosuppression, nephrotoxicity, hypertension,
dyslipidemia

Question 25

CYCLOSPORINE
*Therapeutic drug monitoring

Answer 25

*Trough concentration in whole blood (usually 75 – 450 mcg/L or ng/mL);
target based on indication and time post-transplant. Target typically higher
immediately post-transplant and gradually reduced over 3-4 months.
*Rate of concentration target change dependent on patient’s clinical status.
*C2 level (i.e., 2 hr post-dosing): more accurate for estimating exposure
Limited sampling strategies (Rarely used. For AUC estimation, aiming for AUC
> 4,400 ngh/mL to minimize rejection)
*Note: concentrations obtained from different analytical assays are not
interchangeable. Immune assays usually report higher concentrations (crossreactivity). Target ranges tailored to each specific assay.

Question 26

CYCLOSPORINE
*Pharmacogenomics

Answer 26

*“conflicting evidence regarding association between
CYP3A5 variation and drug plasma levels
of…cyclosporine”
*“…the clinical relevance of CYP3A5 pharmacogenetics
for cyclosporine metabolism remains unclear”
* Rodriguez-Antona et al. Clin Pharmacol Ther. 2022; doi. 10.1002/cpt.2563. In Press.
*Kiang: no definitive data suggesting genotype-guided
dosing of cyclosporine can improve efficacy or reduce
toxicity in 2023, yet

Question 27

RI, a 39-year-old, 51kg woman, received an unrelated renal
transplant over a decade ago. Her serum creatinine had been stable
in the range of 50–60 µmol/L. She has been receiving cyclosporine
modified orally 125mg BID. Trough cyclosporine concentrations have
been ~ 75 ng/mL (target 75 –125). Her last clinic appointment was 3
weeks ago. Other immunosuppressive medications included
prednisone 10mg/day and mycophenolate mofetil 1g po BID. She
returned to the clinic yesterday complaining of increasing fatigue
since her last clinic appointment. Blood and urine cultures were
taken, and she was admitted to the hospital with a serum creatinine
of 120 µmol/L. How would you adjust RI’s cyclosporine dose to
increase cyclosporine concentration to approximately 125 ng/mL

Answer 27

Graft rejection or cyclosporine toxicity?
Renal ultrasound / biopsy: if rejection, then additional steroid-pulse or
rejection therapy (i.e., ATG) may be needed
Cyclosporine toxicity? Concentration would usually be higher
Assume linearity and proportionality,
Desired dose = Css desired / Css current * current dose
Desired dose = 125 / 75 * 125mg = 208mg → 200mg
Desired dose =~ 200mg PO BID
When would you order a cyclosporine concentration?

Question 28

ER, a new 78kg liver transplant patient, is receiving 200mg/day of
cyclosporine as a continuous IV infusion (patient was intolerant to
tacrolimus). Currently, his hepatic function tests appear to be
stable, and for the past 3 days, he has been improving clinically
with steady-state trough cyclosporine concentrations of
approximately 300 ng/mL (target 250–400). What would be an
appropriate oral cyclosporine (modified) dose for ER?

Answer 28

Mean bioavailability of cyclosporine modified ~ 30%
Give an oral dose that is 3x the parenteral dose.
200mg/day x 3 = 600mg/day or 300mg PO BID
Monitor trough concentrations at steady-state

Question 29

SS is a 65-year-old female patient 20 days post renal transplant
receiving cyclosporine (Neoral) treatment. SS is currently receiving
600 mg of cyclosporine po daily (divided into 2 doses). The patient’s
trough cyclosporine concentration, drawn this morning, was 470
ng/mL (assuming your institutional target is 350-450 ng/mL within 1-
month post-transplant or 750 ng/mL as the “C2” level). The
previous level drawn 5 days ago was 440 ng/mL.
The resident MD wants your advice before rounds on what you
would recommend. He asks you if the team should reduce the dose.
What additional information would you need to provide your
recommendation

Answer 29

Questions you would ask the patient / RN:
Have you received any new (interacting) medications in the past few days?
Have you changed your diet?
When was the concentration drawn? Was it a true trough level? Were the
concentrations drawn at the same time relative to dose?
Is the patient exhibiting any side effects/signs of toxicity (hypertension, tremor?)
What’s the patient’s renal function (stable?)
Consideration: there is a higher risk of rejection within the 1st month posttransplant. There is variability in lab measurements. Keep same dose and redraw
steady-state level within a few days if no other apparent causes and if no evident
side effects observed.

Question 30

SAMPLE FINAL EXAM QUESTION
*Which of the following drugs can potentially decrease the
clearance of cyclosporine? Select all correct answers
1) dihydropyridine calcium channel blockers
2) itraconazole
3) rifampin
4) macrolide antibiotics (e.g., erythromycin)
5) mycophenolate

Answer 30

itraconazole
macrolide antibiotics (e.g., erythromycin)