TRANSPLANT 3 Flashcards
SIROLIMUS
indication
*Mechanism
*Indication:
* Kidney (primary indication)/liver/heart transplantation
*Not 1st line therapy in transplant combinatorial pharmacotherapy
*Used in patients intolerant to calcineurin inhibitors (nephrotoxicity) and for patients
with evident skin cancer.
*In combination with lower dose calcineurin inhibitors (+prednisone) or calcineurin
inhibitor-free regimens (+MPA & prednisone)
* Start the drug only > 3 months post-transplant due to delayed wound healing
effects (i.e., typically not used in de novo patients)
* Tedesco-Silva et al. Clin Transplant. 2019; 33:e13464
*Mechanism:
*Binds to FKBP12, but the complex does not inhibit calcineurin activity
*Sirolimus-FKBP12 inhibits the mammalian target of rapamycin (mTOR) – a
protein kinase responsible for the G1S cell cycle progression
* T-cell proliferation by blocking cell cycle progression. Anti-cancer effects
IROLIMUS
*Dosing and formulations:
Some centres do not provide
the loading dose, but rather
will overlap
immunosuppressants
Tablet and solution formulations
not interchangeable
However:
The 2mg dose is roughly
equivalent between the two
formulations
SIROLIMUS
Absorption:
Distribution
Absorption:
*Bioavailability ~ 15% (oral solution) and ~19% (tablet)
*Fatty food Cmax ~ 30% (consistency is key to minimize variation)
*Grapefruit juice CYP3A4 and p-glycoprotein bioavailability
*Tmax ~ 2 hours
Distribution:
*Blood:plasma ratio of ~37:1
*Use whole blood for therapeutic drug monitoring
*~92% bound to albumin
*Contraindicated in pregnancy
SIROLIMUS
*Metabolism and Excretion
*Extensively metabolized by intestinal/hepatic CYP3A4/5 and
transported by p-glycoprotein drug / gene interactions
* Primarily fecal elimination
*CL: 0.14-0.17 L/hr/kg
*Half-life: 62 hours with normal liver function, and up to 110 hours with
liver dysfunction (how many days to steady-state?)
*Reduce dose by 1/3 in patients with liver dysfunction
*Loading dose recommended due to length of time required to reach
steady-state
SIROLIMUS
*Adverse effects:
*Concentration dependent:
* neurotoxicity associated with calcineurin inhibitors
*Myelosuppression thrombocytopenia, leukopenia, anemia (may be
transient; observed within first weeks of initiating drug)
*Hypercholesterolemia / hypertriglyceridemia (may require
pharmacotherapy; observed within first few months)
* lipoproteins & lipoprotein lipase
*GI toxicities / mouth ulcer (up to 60% of patients)
*Lymphocele: lymph fluid drains out and accumulates in cavities
*Hypokalemia
*Delayed wound healing / hepatic artery thrombosis
SIROLIMUS
*Adverse effects:
*Concentration independent:
*Anaphylaxis, dermatitis, angioedema, vasculitis
*Interstitial lung disease, arthralgia
SIROLIMUS
*Drug-Drug interactions:
*Essentially the same as tacrolimus and cyclosporine (via
CYP3A4 and p-glycoprotein modulations)
*Cyclosporine (modified) sirolimus Cmax and AUC (and
vice versa)
*Competitive inhibition of CYP3A4 and p-glycoprotein
*Space / separate the co-administration apart
*Interaction not observed with tacrolimus
Tacro does NOT inhibit CYP3A5 and PGP
SIROLIMUS
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Drugs that can cause myelosuppression, hypercholesterolemia, and
hypertriglyceridemia
SIROLIMUS
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Clinically relevant Pharmacodynamic (PD) interactions:
*Drugs that can cause myelosuppression, hypercholesterolemia, and
hypertriglyceridemia
SIROLIMUS
*Therapeutic drug monitoring
Pharmacogenomics
*Trough concentration in whole blood (usually 4 – 15 ng/mL or mcg/L); targets
are centre-specific and based on indication, time post-transplant, and
concurrent immunosuppressants.
Insufficient evidence as of the year 2023 to recommend
genotype-guided dosing of sirolimus in transplant patients
AB is to begin an immunosuppression regimen consisting
of cyclosporine modified 300mg PO BID, sirolimus 2 mg
PO daily, and prednisone taper. Does it matter when
AB takes his sirolimus?
When sirolimus is given simultaneously with cyclosporine, Cmax
and AUC of sirolimus can increase up to 1 – 3 fold.
When sirolimus is administered 4 hours after cyclosporine,
Cmax and AUC increase is lower.
Labeling suggests that sirolimus be administered 4 hours after
cyclosporine.
Consistency is key.
AB is being given sirolimus in a liquid formulation during his
hospital stay. He mixes his daily dose with orange juice but
does not like the taste. Can AB be switched to the tablet
formulation?
Liquid formulation can only be mixed with water or orange
juice and consumed right away
Other liquids should not be used due to lack of stability data
2mg conversion from liquid to oral is generally accepted
bioequivalent (other doses are not)
Monitor sirolimus trough concentrations at steady-state
CG, a stable kidney transplant recipient, was taking a stable
regimen of cyclosporine modified 200mg PO BID, sirolimus 2mg
PO daily, and prednisone 10mg PO daily. Her steady-state
cyclosporine concentration was 200 mcg/L (trough) and steadystate sirolimus concentration was 9 mcg/L on this regimen. CG was
started on fluconazole 200mg po daily to treat a fungal infection.
Two weeks later, her platelet count decreased from 200K/µL to
75K/µL, and her white blood cells decreased from 7x10^9/L to
2.5x10^9/L. Her latest cyclosporine blood concentration was 400
mcg/L (trough), and sirolimus concentration was 20 mcg/L. What
could account for her thrombocytopenia and leukopenia and
elevated cyclosporine and sirolimus concentrations? How would you
manage this interaction?
How’s the patient’s renal function?
Is the patient exhibiting signs of toxicities from cyclosporine and sirolimus?
Double check to make sure levels are drawn appropriately on time (i.e., true trough
concentrations) – check the MAR
Are there dietary and medication changes other than fluconazole?
Fluconazole is an inhibitor of CYP3A4 and p-glycoprotein and can both cyclosporine
and sirolimus concentrations
sirolimus thrombocytopenia and leukopenia
Assess the need and duration for fluconazole. If prolonged usage is needed and no
alternative antifungal (with no interaction), then consider dose reducing sirolimus.
Reducing sirolimus dose by ½ reduce the steady-state concentrations by ~ ½; but it
would take at least 2 weeks to reach steady-state.
Also need to re-adjust the sirolimus dosage again after stopping fluconazole.
How about cyclosporine dosage?
EVEROLIMUS
*Similar indications and mechanisms of actions as sirolimus. Also
used in liver transplant patients.
*Dosing and therapeutic targets ranges are specific to everolimus.
*Distinctive pharmacokinetic profiles. Substrate of CYP3A4 and pglycoprotein. Much shorter half-life: 18-35 hours.
*Similar side effect profiles and drug interaction profiles
*Slightly less effect on wound healing; thus, can be started earlier posttransplantation
*Less likely to neurotoxicity associated with tacrolimus or cyclosporine (vs.
sirolimus)
PREDNISONE
*Indication:
mechanisms
*Indication:
*Solid organ transplantation (kidney, liver, heart, lung) and many
other inflammatory conditions
*Prednisone is primarily used in transplantation. Others include
prednisolone, methylprednisolone
*Mechanisms:
*Multiple targets with translocation / function of proinflammatory transcription factors (activator protein-1 or nuclear
factor-B) cytokine production (IL-1, IL-2, IL-3, IL-6, interferon
, tumor necrosis factor) overall inflammation
* T-cell activation, chemotaxis of neutrophils and monocytes,
number of monocytes, macrophages, eosinophils, and basophils
PREDNISONE
*Dosing:
Steroid avoidance: only methylprednisolone peri-transplant (usually for patients with low
immunologic risks)
Rapid steroid withdrawal: prednisone withdrawn quickly post-transplant over 7 days (usually
for patients with low immunologic risks)
Early steroid withdrawal: prednisone withdrawn over the first few months post-transplant
(usually for patients with lower immunologic risks)
Withdrawal can increase the risk of acute rejection but may not affect longer term outcomes
(active area of research) in select patients
Woodle ES, Gill JS, Clark S, Stewart D, Alloway R, First R. Early corticosteroid cessation vs long-term corticosteroid
therapy in kidney transplant recipients: Long-term outcomes of a randomized clinical trial. JAMA Surg. 2021;156(4):307-
14.
Low dose steroid maintenance: prednisone never withdrawn, but tapered to the lowest
maintenance dose possible (i.e., 5-10 mg/day)
PREDNISONE
*Dosing and formulations
Rates of steroid taper differs between centres and physicians.
* Tailored to the specific patient.
* Example for steroid-maintenance regimen: methylprednisolone
0.5mg/kg IV daily until patient tolerating PO, then change to
prednisone 0.5 mg/kg (max dose 35mg) po daily. Taper as
directed.
* Administered in the am (7-8am) to mimic body’s diurnal release of
cortisol.
PREDNISONE
Absorption:
Distribution
Absorption:
*Well-absorbed, bioavailability ~90%
*Tmax ~1-3 hr
*Effects of food on absorption not well-characterized; may Tmax
*Take with food to GI upset
Distribution:
*Requires bioactivation to prednisolone
*Vd ~ 0.2-0.7 L/kg for prednisolone (non-linear kinetics; higher Vd with
larger doses)
*Saturable binding to albumin and transcortin (50-90%; increase free fraction
with larger doses) – discordance between total and free concentrations
*Can distribute into the placenta and breast milk
PREDNISONEPREDNISONE
*Metabolism and Excretion
*Metabolism and Excretion
*Phase I (CYP3A4/5, hydroxylation) and Phase II (sulfonation,
glucuronidation) hepatic enzyme metabolism of prednisolone
*Renal elimination
*Clearance: 0.55-0.79 L/hr/kg ( total clearance with larger dose
>20mg – why??) – remember Pharm303 clearance concepts
*Half-life: 2-4 hours (prednisolone; how many days to steady-state? Can
steady-state ever be achieved??)
*Pharmacodynamic effects are much longer (hence, can be administered
daily)
these are those daily in the morning. so based on that. Would the patient ever reach steady state?
No. So it’s kind of weird, because it does it small doses daily. and
the body clears it off within
10 h. Ish right? And but you’re You’re not gonna do it until 24 h later. So in essence you’re not. You’re never reaching steady state
Fx of chemokines last much longer
NEVER REACH SS
PREDNISONE
*Adverse effects (head-to-toe approach)
*CNS toxicity: nightmares, psychosis, depression
*Ocular: intraocular pressure, glaucoma, cataract
*Adrenal suppression: hypothalamic-pituitary-adrenal axis secondary
adrenal insufficiency; requires “stress dosing” for surgery, infection, trauma
*Cushingoid appearance: truncal obesity, facial adipose tissue (“Moon
face”), dorsocervical adipose tissue, striae, acne, hirsutism
*Cardiovascular: hypertension, dyslipidemia, fluid retention, K+, Na+,
arrhythmias (interacts with cyclosporine, mTOR inhibitors)
*Endocrine: hyperglycemia (interacts with tacrolimus and antidiabetics)
*Neuromuscular & skeletal: osteoporosis, bone fractures, myopathy,
osteonecrosis
*GI: peptic ulcer disease, gastritis, esophagitis
*Infections: viral, bacterial, opportunistic (causes leukocytosis)
* growth rate in children
PREDNISONE
*Pharmacokinetic Drug-Drug interactions:
via CYP3A4 and p-glycoprotein
* CYP3A4 / p-glycoprotein inducers (phenobarbital, carbamazepine, phenytoin, rifampin)
prednisolone concentrations
* CYP3A4 /p-glycoprotein inhibitors (see list from tacrolimus slides) may concentrations
*Prednisone/prednisolone can potentially induce phase I and
Phase II enzymes
*Potentially clearance of tacrolimus, cyclosporine, sirolimus, and
mycophenolate
*Potential explanation for the significant variability in MPA clearance within
the first few months of transplant (during prednisone taper)
PREDNISONE
*Drug-Drug interactions:
*Clinically relevant Pharmacodynamic (PD) interactions
*Therapeutic drug monitoring
*See head-to-toe list of pharmacodynamic side effects
*Not commonly done due to the wide therapeutic range
PREDNISONE
*Pharmacogenomics
No definitive data suggesting genotype-guided dosing of
prednisone can improve efficacy or reduce toxicity in
transplant patients in 2023
SAMPLE FINAL EXAM QUESTION
*Which of the following is correct about the pharmacogenomics of
immunosuppressants in transplantation in the year 2022
1) CYP3A5 genotyping is recommended for patients to be prescribed tacrolimus,
cyclosporine, and sirolimus
2) CYP3A5 genotyping is recommended for patients to be prescribed
mycophenolate
3) CYP3A4 genotyping is recommended for patients to be prescribed tacrolimus,
cyclosporine, and sirolimus
4) CYP3A4 genotyping is recommended for patients to be prescribed
mycophenolate
5) None of the above
6) All of the above
5) None of the above
* Not a lot of evidence today, right? So none of those above.
