CONTENTS

• Disclaimer – Still consult transplant medicine
• Mycophenolate
• Azathioprine
• Calcineurin inhibitors (tacrolimus, cyclosporine)
• Sirolimus
• Questions & discussion

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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disclaimer: for organ recipients, always consult with transplant medicine

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Anti-rejection medications should always be managed in conjunction with an organ transplantation team. If the patient's transplantation physicians don't work at your hospital, then their transplantation coordinator and physicians should still be contacted and involved in management decisions. The discussions below are intended to provide a general understanding of immunosuppressive medications, but should not replace involvement of transplantation experts.

information to obtain prior to calling transplant medicine ☎️

• Baseline information:
  • What is the patient's home medication regimen?
  • If the patient is on medications that are titrated against drug levels (e.g., tacrolimus), what is the patient's target drug level?
• Has the patient missed any doses?
• Are there any changes in renal or hepatic function?
• Are there any changes in medications that have drug-drug interactions with immunosuppressives (either initiation or discontinuation)?
  • Run the patient's medication list through a drug interaction checker program: 🧮
• Current drug level(s)? Note that drug levels should generally be a trough level, so a random level will often be unhelpful.

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mycophenolate

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#1/7) indications & dosing 💊

• Transplantation:
  • Mycophenolate has generally replaced azathioprine due to greater potency and specificity in targeting lymphocytes.
  • Lung transplantation: 1,000 – 1,500 mg BID.
• CTD-ILD (connective tissue disease-related ILD):
  • Mycophenolate is increasingly a preferred agent for several reasons:
    • From an evidence-based standpoint, mycophenolate has been shown to be equally as effective as cyclophosphamide for patients with scleroderma. (27469583) 
    • Mycophenolate is generally very well tolerated (aside from mild gastrointestinal side effects).
    • Mycophenolate may be useful in disorders in which cellular NSIP or OP are prominent. (28552544)
  • Drawback: Mycophenolate may be less effective than azathioprine for joint involvement.
  • The starting dose is often 500 mg BID. If this is tolerated, the dose may be up-titrated at two-week intervals to ideally target a dose of 1,500 mg BID (the dose used in the Scleroderma Lung Study). (Shah 2019) 
  • Myositis-associated ILD: 2000-3,000 mg/day in two doses may be utilized. (36764512)
• Lupus nephritis.
• Sarcoidosis: Doses of 1 – 1.5 grams twice daily are typically used. (BTS 2020 guidelines)
• Renal dysfunction:
  • When the GFR is <30 ml/min, concentrations can double, which can necessitate dose adjustment. (32055040) If GFR <25 ml/min, the dose shouldn't exceed 1 gram every 12 hours. (Medscape) Concentrations of the inactive glucuronide metabolite may increase, causing gastrointestinal side effects. 
• Hepatic dysfunction: no dose adjustment is recommended. (28784214)

#2/7) monitoring

• Complete blood count.

#3/7) drug interactions

• Cyclosporine may reduce serum concentrations of mycophenolate (by limiting biliary excretion and enterohepatic recycling).
• Valganciclovir combined with mycophenolate may produce a high risk of leukopenia. (30927190)
• Medications can interfere with drug absorption:
  • Proton pump inhibitors may impair the absorption of mycophenolate mofetil, but not enteric coated mycophenolate sodium. (32055040)
  • Avoid administration with aluminum or magnesium-containing antacids.
  • Avoid coadministration with cholestyramine or sevelamer (these interfere with enterohepatic metabolism and drug absorption).
• Numerous other interactions exist; the full list is here: 💊

#4/7) pharmacology

pharmacology of mycophenolate mofetil

• Bioavailability is variable across different formulations:
  • CellCept™️ tablets are 94% bioavailable. (32055040) 
  • MyFortic™️ tablets are 72% bioavailable.
  • An oral suspension and intravenous formulations may also be available.
• Maximal absorption occurs after ~1.5 hours. (32055040)
• Protein binding is high (82-97%). (32055040)
• Metabolic pathway includes two metabolites, as listed below. The half-life of various intermediaries may vary between individuals, leading to large variation in plasma levels. (32055040)
  • [1] Mycophenolate mofetil is a pro-drug of mycophenolic acid. Mycophenolate mofetil is hepatically metabolized with a half-life of 18 hours.
  • ⬇️ Converted into:
  • [2] Mycophenolic acid (active drug) undergoes enterohepatic circulation with eventual hepatic metabolism. It has a half-life of 8-16 hours.
  •  ⬇️⬆️
  • [3] Mycophenolic acid glucuronide (inactive metabolite) is renally excreted with a half-life of 13-17 hours. Although inactive, mycophenolic acid glucuronide accumulation can be clinically significant. First, mycophenolic acid glucuronide may undergo biliary excretion, deconjugation by intestinal flora into mycophenolic acid, and subsequent reabsorption. (28784214) Second, mycophenolic acid glucuronide competes with mycophenolic acid for protein binding, thereby increasing the free concentration of mycophenolic acid (which is the biologically active form of the drug). (34874841)

pharmacology of mycophenolate sodium

• Mycophenolate sodium is also a pro-drug of mycophenolic acid. It might have a reduced incidence of gastrointestinal side effects.
• 720 mg of mycophenolate sodium is equivalent to 1000 mg of mycophenolate mofetil. (27254639)

#5/7) contraindications

• Contraindicated in pregnancy (two forms of contraception should be utilized until more than 6 weeks from discontinuation). (27254639)

#6/7) side effects

• Mycophenolate is generally well tolerated.
• Gastroenterological side-effects are commonly problematic (nausea/vomiting, diarrhea, abdominal pain).
  • Side effects are related to the peak drug level. This may be managed by dividing the dose into three doses per day. (30927190) Another alternative is mycophenolic acid (which has slower absorption, leading to lower peak levels).
  • CMV colitis has been reported, but it is much less likely.
• Myelosuppression is a rare complication (less problematic than with azathioprine). Various manifestations of myelotoxicity may include pure red cell aplasia or neutropenia.
• Hypogammaglobulinemia has been reported when mycophenolate is combined with other immunosuppressive agents.
• Transaminase elevation may occur rarely.
• Dry cough and dyspnea may rarely occur within the third month of therapy. (30927190)
• Acute inflammatory syndrome: (30927190)
  • Paradoxical inflammatory reaction involving fever, arthralgias, arthritis, muscle pain, and elevated CRP (C-reactive protein).
  • Occurs within weeks to months of treatment initiation or dose escalation.
  • After holding mycophenolate, improvement should be seen within 1-2 days.
• Increased risk of malignancy (lymphoma, skin cancer).
• Increased risk of certain infections:
  • Reactivation of HBV, HCV, HSV, or CMV.
  • Progressive multifocal leukoencephalopathy. (32055040)
  • Urinary or respiratory tract infection.

#7/7) mechanism of action

• (1) Mycophenolate inhibits the formation of guanine nucleotides via the de novo synthetic pathway, a pathway which is relied upon by lymphocytes. This makes B- and T-lymphocytes a relatively specific target of mycophenolate. (37126103 However, this may also suppress proliferation of fibroblasts – a beneficial effect in many rheumatologic disorders to prevent ongoing fibrosis. One in vitro study detected anti-fibroblast effects from mycophenolate or tacrolimus (but not methylprednisolone, cyclosporine, azathioprine, or everolimus). (32055040)
• (2) Mycophenolate also affects histone modifications in CD4+ T-cells, which down-regulates the CD40 ligand (CD40L) that is involved in co-stimulation of antigen-presenting cells. (32055040)

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azathioprine

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#1/7) indications & dosing 💊

• General approach:
  • Azathioprine is often started at low dose (~50 mg) and up-titrated by 50 mg increments every 2-4 weeks if tolerated (without the development of leukopenia). The maximal dose is ~2.5-3 mg/kg/day. Azathioprine is typically administered once daily.
  • Testing of thiopurine S-methyltransferase enzyme (TPMT) activity may facilitate more accurate dose titration. Patients with low TPMT activity are more sensitive to azathioprine (with increased risk of myelosuppression). (33271551) BTS guidelines for sarcoidosis recommend measuring TPMT levels prior to starting azathioprine. (BTS 2020 guidelines) About 10% of patients have intermediate levels of TMPT (which would suggest initiating azathioprine at a lower dose) and 0.3% have very low levels of TMPT (which would suggest considering an alternative therapy).
• Transplantation:
  • Azathioprine has largely been replaced by mycophenolate mofetil.
  • Lung transplantation: target ~2 mg/kg/day.
• Rheumatology:
  • Lupus.
  • Myositis.
  • Scleroderma.
  • ANCA vasculitis (after remission induction).
• ILD (especially connective tissue disease-associated ILD):
  • In CTD-ILD, azathioprine may be helpful for control of both interstitial lung disease and also synovitis.
  • Usual studied doses range from ~2-2.5 mg/kg/day (maximum 200 mg/day). (36764512; 33271551)
• Sarcoidosis:
  • Azathioprine is generally used as a second-line therapy (after methotrexate). However, both agents seem to have the same efficacy overall.
  • Usual dosing strategy: (BTS 2020 guidelines)
    • Start at 50 mg/day & check TPMT levels (discussed above).
    • Increase by 25 mg every 2-3 weeks.
    • Target dose is 2 mg/kg/day.
• Renal insufficiency: Dose reduction is needed.

#2/7) monitoring

• Complete blood count.
• Liver function tests.
• (Drug levels of therapeutic erythrocyte 6-thioguanine can be occasionally helpful.)

#3/7) drug interactions

• Allopurinol or febuxostat block the degradation of azathioprine. Azathioprine dose must be reduced by 60-75% (although ideally these drugs just shouldn't be used together).
• Numerous other drug interactions exist; the complete list is here: 💊

#4/7) pharmacology

• Bioavailability is highly variable (30-80%). (32055040)
• Protein binding is ~25%. (32055040)
• Azathioprine may be metabolized in the liver via different, competing pathways (figure below).
  • Xanthine oxidase and TPMT metabolize azathioprine into inactive compounds. Genetic variations in TMPT determine how sensitive an individual patient is to the effects of azathioprine.

#5/7) contraindications

• Increased risk of bone marrow failure:
  • Myelodysplasia or pre-existing cytopenias.
  • Prior treatment with alkylating agents.
• Pregnancy, lactation (class D in pregnancy; however, continuation of azathioprine during pregnancy may be considered).

#6/7) side effects

• Myelosuppression:
  • Myelotoxicity from azathioprine may develop at any time during therapy. It may occur either suddenly or over several months. (30927190)
  • Leukopenia is predominantly seen, but macrocytic anemia and/or thrombocytopenia may also occur.
• Gastrointestinal effects:
  • Cholestatic hepatitis may rarely occur (liver function tests should be followed).
  • Gastrointestinal intolerance, including nausea and vomiting (divided doses may help with this, or administration after meals).
  • Pancreatitis.
  • Nausea, vomiting, or diarrhea may occur.
• Increased risk of malignancy (including lymphoma and non-melanoma skin cancers). (32055040)
• Increased risk of infection, including progressive multifocal leukoencephalopathy.
• Hypersensitivity reaction (may involve fever, hypotension, acute leukopenia, rash, hepatitis). (32055040)
• Pulmonary toxicity is rare (<1%; includes pulmonary fibrosis, hypersensitivity-type reactions, or diffuse alveolar damage).

#7/7) mechanism of action

• Azathioprine has a more powerful effect on nucleotide metabolism than mycophenolate:
  • Azathioprine inhibits the de novo purine synthesis pathway (similar to mycophenolate). Azathioprine also inhibits the salvage purine synthesis pathway, leading to a broader inhibition of DNA synthesis. (27254639) 
  • Toxic thioguanine nucleotides are incorporated into DNA and RNA, which is thought to mediate the cytotoxic effects of azathioprine as well as its mutagenic effects (azathioprine is potentially carcinogenic, whereas mycopheonlate isn't). (32055040, 30927190) Mycophenolate is associated with an increase in some malignancies, but this reflects ineffective immune surveillance for cancer, rather than direct mutagenesis. 
• In vitro, azathioprine may cause stimulated T-cells to undergo apoptosis. This may reflect an interaction of 6-mercaptopurine with T-cell regulation. (32055040) 

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calcineurin inhibitors (tacrolimus, cyclosporine)

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#1/7) indications & dosing 

some general points:

• Dose is adjusted based on trough levels. ⚠️ In transplant patients, the target level depends on the organ being transplanted and the time since transplantation. This will often be tailored to the patient. Some rough targets are listed below, but these will not apply to all patients.
• Dosing should be spaced precisely q12 hours (not “twice daily”). (27254639)

tacrolimus 💊

• Note: levels >25 ng/ml are considered toxic.
• Lung transplant:
  • <1 year:
    • Target 8-15 ng/ml. (36774158)
    • Initial dose is 0.1 mg/kg per day in two divided doses q12hr. Levels should be measured daily in the immediate postoperative period, since frequent adjustments may be needed. (36774158)
  • >1 year: Target 6-8 ng/ml.
• Kidney or liver transplant:
  • Initiation: Target 12-19 ng/ml.
  • Maintenance: Target 6-12 ng/ml.
• Heart transplant:
  • Initiation: Target 19-25 ng/ml.
  • Maintenance: 6-12 ng/ml.
• Myositis-related ILD:
  • Target trough varies between studies, in the range of 5-20 ng/ml. (33179395) A lower target trough (e.g., ~5-10 ng/ml) may be safer once the disease has stabilized. For induction therapy in uncontrolled severe disease, a higher target trough might be more effective (e.g., ~10-15 ng/ml). (34602377, 36764512)
  • The typical starting dose is 0.075 mg/kg/day, divided into two doses given q12hr. (31539061, 33179395, 26328518) The dose is subsequently adjusted based on levels. 
• Renal failure:
  • Tacrolimus is hepatically metabolized, so the drug level won't be affected.
  • However, tacrolimus is potentially nephrotoxic – so dose reduction may be advisable in the context of acute kidney injury. This is discussed further in the the section below on side effects.
• Hepatic dysfunction:
  • Mild: no adjustment.
  • Moderate: monitor drug levels and adjust accordingly.
  • Severe (Child-Pugh score >10): dosage adjustment recommended.

cyclosporine

• Lung transplant:
  • <1 year:
    • Target trough level is 250-350 ng/ml.
    • Initial dose is 5 mg/kg per day in two divided doses. (36774158)
  • >1 year: 200-300 ng/ml.
• Kidney transplant:
  • 0-6 months: Target 250-375 ng/ml.
  • 6-12 months: Target 200-300 ng/ml.
  • >12 months: Target 100-150 ng/ml.
• Cardiac transplant:
  • 0-6 months: 250-350 ng/ml.
  • 6-12 months: 150-250 ng/ml.
  • >12 months: 100-150 ng/ml.
• Liver transplant:
  • Initiation: 250-350 ng/ml.
  • Maintenance: 100-200 ng/ml.
• Myositis-related ILD: Target 100-150 ng/ml or 150-200 ng/ml, depending on severity and prognosis. (34602377)
• DRESS syndrome: A series from Harvard reported utilizing 3-5 mg/kg divided twice daily for 7 days, followed by 1.5-2.5 mg/kg divided twice daily for seven days. (32159726) Alternatively, a series from the University of Colorado reported generally using 4-5 mg/kg divided twice daily for 5-7 days. (37632913) In practice, the duration of therapy may be adjusted based on clinical response and the presence of ongoing organ failure(s). 

#2/7) monitoring

• Blood pressure.
• Renal function and electrolytes (including Ca/Mg/Phos).
• Glucose levels.

#3/7) drug interactions

• Some of the following agents are absolutely contraindicated; in other cases coadministration may be reasonable with close monitoring of drug levels.
• ⚠️ If a patient who is on a stable tacrolimus regimen is already taking one of these medications chronically, then the interacting medication should ideally not be changed (so that the patient's drug regimen remains stable).
• Drugs that increase calcineurin levels include:
  • Calcium channel blockers (diltiazem, verapamil, nicardipine).
  • Azole antifungals.
  • Macrolides other than azithromycin (erythromycin, clarithromycin).
  • Amiodarone.
  • Ranolazine.
  • Protease inhibitors.
  • Selective serotonin reuptake inhibitors.
  • Grapefruit juice.
• Drugs that decrease calcineurin levels include:
  • Anti-seizure medications (phenytoin, phenobarbital, carbamazepine).
  • Rifampin.
  • Isoniazid.
  • Dexamethasone.
  • Trimethoprim.
  • St. John's Wort.
• Numerous other drug-drug interactions exist, listed here: 💊

#4/7) pharmacology

tacrolimus

• Bioavailability is low (20-25%).
  • P-glycoprotein within intestinal cells pumps tacrolimus out of the cells. Any inhibition of p-glycoprotein will increase bioavailability.
  • Astagraf™️ XL is a once daily formulation that is 1:1 convertible to Prograf™️. (27254639)
  • Envarsus™️ XL is a once daily formulation that may be ~20% more potent than Prograf™️. (27254639)
  • For intubated patients, a tacrolimus suspension can be produced from oral tacrolimus capsules and administered via enteral tube (including either a gastric tube or a postpyloric tube). (27254639)
  • Sublingual administration of Protraf™️ or generic tacrolimus may be utilized in patients unable to take medications orally (with a dose conversion of oral:sublingual of 2:1). This may be achieved by opening the capsule and placing contents underneath the patient's tongue for 5-15 minutes, with avoidance of oral intake for the next 15-30 minutes. (27254639)
  • Intravenous tacrolimus may be available (with a dose conversion of oral:IV of 3-5:1). Continuous infusion over 24 hours might reduce adverse effects from intravenous administration. (27254639)
• >99% protein binding (to albumin and alpha-1 glycoprotein). (27254639)
• Metabolism: CYP3A4-mediated metabolism in the liver into inactive metabolites.
• Half-life: 12-15 hours.

cyclosporine

• Oral bioavailability is erratic (historically ~30%). However, some newer formulations may increase bioavailability (e.g., Neoral™️ has ~67% bioavailability). (34874841)
• High protein binding (to lipoproteins). (27254639)
• PO to IV conversion depends on which oral formulation is used (since they have different bioavailability). Unfortunately the intravenous vehicle (polyoxyethylated castor oil) may increase nephrotoxicity. (34874841)
• Cyclosporine is metabolized by the liver, with numerous drug interactions.

#5/7) contraindications

• Simultaneous use of additional nephrotoxins.
• Substantial renal dysfunction (e.g., GFR <40 ml/min). (30927190)
• Pre-existing thrombotic microangiopathy.
• Pregnancy.

#6/7) side effects

• Renal failure
  • This includes acute tubular necrosis, or a thrombotic microangiopathy.
  • Calcineurin-induced nephrotoxicity is a major cause of chronic kidney disease after transplantation. (27254639)
  • One suggested approach to acute kidney injury is to reduce the calcineurin dose by 25% if the creatinine increases by 30-50%, reduce the calcineurin dose by 50% if the serum creatinine increases by >50%, and to transiently hold the calcineurin inhibitor if the serum creatinine increases by >70%. (30927190)
• Electrolyte abnormalities:
  • Type IV renal tubular acidosis (hyperkalemia, hyperchloremic metabolic acidosis).
  • Hypomagnesemia, hypophosphatemia.
  • Hypocalcemia.
  • Hyperuricemia.
• Hypertension.
• Hyperglycemia (including diabetes).
• Hyperlipidemia.
• Neurologic:
  • PRES (posterior reversible encephalopathy syndrome).
  • Tremor.
  • Peripheral neuropathy, burning paresthesia.
  • Headache.
  • Depression.
  • Insomnia, confusion.
• Gastrointestinal side effects:
  • Gastroparesis.
  • Diarrhea.
• Anemia.
• Opportunistic infection, including:
  • Legionella.
  • Nocardia.
  • Aspergillus and other hyaline molds.
  • Mucorales spp.
  • CMV.
  • BK virus-induced nephropathy.
  • Endemic fungi. (32561442) 
• Adverse events that are specific to cyclosporine:
  • Hirsutism.
  • Gingival hyperplasia.

#7/7) mechanism of action

• Tacrolimus interrupts T-cell activation and the production of IL-2 (due to effects on calcineurin and MAPK (mitogen-activated protein kinase) pathways). (37126103) 

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sirolimus

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#1/7) indications & dosing 💊

• Target the trough level (>16 nM is toxic).
• Transplantation:
  • Calcineurin inhibitors are usually front-line, but an mTOR inhibitor may be superior in patients with renal dysfunction.
  • Lung transplant: target 6-12 ng/ml.
  • Kidney transplant: target 4-14 ng/ml.
• Lymphangioleiomyomatosis: target is variable, often ~5-10 ng/ml.
  • The starting dose may range between 1-2 mg daily.
  • The landmark MILES trial initiated sirolimus at 2 mg/day and titrated the dose to achieve a target trough level of 5-15 ng/ml (with most patients actually achieving a trough level between 5-10 ng/ml). (21410393) 
  • Low-dose sirolimus (1 mg/day, target blood trough <5-10 ng/ml) might have efficacy equivalent to higher doses.
  • ⚠️ Sirolimus may be held temporarily for acute illness involving infection or surgery (since it may interfere with wound healing).
• Renal dysfunction: Dose adjustment isn't generally necessary.
• Hepatic dysfunction:
  • Child-Pugh A or B cirrhosis: reduce dose by 33%.
  • Child-Pugh C cirrhosis: reduce dose by 50%.

#2/7) monitoring

• Lipid panel.

#3/7) drug interactions

• Sirolimus is a substrate for CYP3A4 and P-glycoprotein. (27254639)
• Sirolimus has the same drug interactions as calcineurin inhibitors (see the section above).
• Co-administration with ACE-inhibitors may increase the risk of angioedema.
• For a complete listing of drug interactions: 💊

#4/7) pharmacology

• Bioavailability is 14% (oral solution) or 41% (tablet).
• Protein binding is 92%.
• Metabolism occurs in the liver via CYP3A4.
• Half-life is ~60 hours.
• An oral solution is available for administration via gastric or postpyloric enteral tubes. (27254639)

#5/7) contraindications

• Surgery (sirolimus may interfere with wound healing).
• Hypersensitivity to sirolimus or macrolide antibiotics.
• History of bradykinin-mediated angioedema (e.g., due to ACE inhibitors).
• Sirolimus is classified as category C in pregnancy. Its use is not well explored in the treatment of pregnant patients. (32505325)

#6/7) side effects

side effects 

• Hypertriglyceridemia.
• Cytopenias: thrombocytopenia, leukopenia, anemia, lymphopenia. (28784214)
• Peripheral edema.
• Skin rash, mouth ulcers.
• Gastrointestinal: Diarrhea, nausea, mucositis. (28784214)
• Sirolimus doesn't seem to be substantially nephrotoxic, but it may delay the recovery from acute tubular necrosis. Thus, transitioning from a calcineurin inhibitor to sirolimus may improve renal function. (28784214; 34874841)
• Hypertension.
• Pulmonary toxicity:
  • Interstitial pneumonitis (discussed further below).
  • When utilized early in lung transplantation, sirolimus is associated with bronchial anastomotic dehiscence. Thus, sirolimus is ideally restricted for later time periods following lung transplantation.
• Opportunistic infections: increased rates of cryptococcus, pneumocystis, BK virus-associated nephropathy, and progressive multifocal leukoencephalopathy. (32561442) 
• Allergy to sirolimus is uncommon but can be severe. Sirolimus might also promote bradykinin-mediated angioedema.

sirolimus induced pneumonitis

• Basics:
  • Histology is variable (most commonly includes organizing pneumonia, lymphocytic interstitial pneumonitis, or pulmonary hemorrhage). (35332071)
  • This may occur in combination with infection (e.g., community-acquired respiratory viruses and/or pneumocystis). (36354934)
  • Pneumonitis appears to be a class effect that may result from any mTOR inhibitor (e.g., sirolimus, everolimus, or temsirolimus), sometimes referred to as “rapamycin lung.” (36354934)
• Epidemiology
  • (1) Lung transplantation:
    • Sirolimus is the most common agent implicated in drug-induced pneumonitis among transplant recipients (including ~10% of kidney transplant patients treated with sirolimus). (Murray 2022) 
    • Usually, pneumonitis begins within 6-12 months following initiation.
  • (2) Lymphangioleiomyomatosis: Pneumonitis is rare, especially with lower dosing of sirolimus.
• Symptoms:
  • Usual symptoms include dry cough, progressive dyspnea, and fatigue.
  • Less frequently, fever or hemoptysis may occur.
• CT usually shows bilateral patchy peripheral consolidations, and reticular and ground-glass opacities. (Murray 2022)
• Bronchoscopy may reveal lymphocytic alveolitis (or, less commonly, diffuse alveolar hemorrhage or eosinophilic alveolitis).
• Management:
  • Discontinuation (or, in some cases, dose reduction).
  • A short course of steroids (e.g., 1 mg/kg/day prednisone) may accelerate resolution in more severe cases. (Murray 2022) 
  • Some patients with sirolimus-induced pneumonitis have tolerated the transition to everolimus. However, everolimus may also cause pneumonitis (which overall appears to be a class effect).

#7/7) mechanism of action

• Sirolimus blocks activation of the cell-cycle specific kinase mTOR, causing cells to arrest in the G1-S phase.

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questions & discussion

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