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7/31/2020

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Contact Information

Drew Silverman, PharmD Pharmacotherapy Specialist in Abdominal Transplantation Tampa General Hospital

Critical Keys to Managing the [email protected] Transplant Patient in the ICU 813-844-7210

th FSHPDrew Silverman,54 Annual Pharm.D; Meeting Pharmacotherapy Specialist in Abdominal Transplantation; Tampa General Hospital August 7-9, 2020 References: 12

FSHP 54th Annual Meeting – August 7-9, 2020 Disclosure Kidney = 358 • I have (or an immediate family member has) a vested Kidney-Pancreas = 10 = 145 interest in or affiliation with any corporate organization Heart = 36 offering financial support or grant monies for this Lung = 34 continuing education activity or with any organization that Total = 584 has a specific interest in the therapeutic areas under Tampa General Hospital Solid Organ Transplants Calendar Year 2019 discussion as follows: Consultant: Veloxis Pharmaceuticals Speaker with honorarium: Veloxis Pharmaceuticals, Pharmaceuticals

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Disease Specific Considerations Outline in the Transplant Patient Objectives • Kidney Transplant 1. Understand the interplay of common diseases seen in critically ill • Recurrent disease transplant patients • Acute Kidney Injury 2. Design a management strategy for treating rejection in the critically ill • Drug clearance patient • Electrolyte disturbances 3. Describe tools for monitoring and assessment of the critically ill transplant • , Hypervolemic Hyponatremia, metabolic acidosis patients • 4. Recognize the pharmacokinetic and pharmacodynamic interactions • Biliary issues between immunosuppressive agents and medications used to manage the • Drug clearance – , decreased biliary transport critically ill transplant patient • Hepatocyte damage 5. Discuss alternative routes of administration for immunosuppressive agents • in the NPO patient • Decreased clearance by up to 66% • Increase tacrolimus half-life 3-fold

References: References: 56

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Disease Specific Considerations mTORs – Interstitial in the Transplant Patient Lung Disease • • Mechanism: Autoimmune response vs. delayed type hypersensitivity? • Decreased EF • No correlation with dose or duration of time therapy • Decreased clearance of high extraction drugs • Diagnosis of exclusion • Cyclosporine, tacrolimus • AKI • Complications • Electrolyte disturbances • • Hyperkalemia, Hyponatremia Interstitial pneumonitis & organizing pneumonia • • Intubated patients need alternative routes of administration • Clinical consideration • Intravenous • Consider mTOR‐I induced interstitial lung disease when patient presents with • unexplained respiratory symptoms • Cyclosporine • R/O all other causes of interstitial lung disease • Steroids • Opportunistic Infections • Tacrolimus- very nephrotoxic • TROLI, Pulmonary interstitial hemorrhage • Sublingual route • Withdrawal of mTOR‐I is therapeutic

References: References: Chajed et al. Respiration. 2006;73:367‐374. 78

FSHP 54th Annual Meeting – August 7-9, 2020 New Onset Diabetes after NODAT Pharmacologic Management Transplant (NODAT) Risk Factors Class Drug Renal Adjustments Comments Exenatide CrCl<30‐ Avoid use

GLP‐1 receptor Liraglutide **Severe renal impairment‐ use with •Cardiovascular benefit agonists Dulaglutide caution •GI ADRs common Albiglutide Semaglutide No dosage adjustment necessary

eGFR<45‐ use not recommended •Cardiovascular benefit Canagliflozin & eGFR <30‐ use CI •Reduced efficacy and increased Empagliflozin SGLT2 inhibitors risk of ADRs in renal impairment eGFR<60‐ use not recommended •Increased risk of dehydration and Dapagliflozin eGFR <30‐ use CI GU infections

Sitagliptin CrCl<50‐  by 50%, <25‐  by 75% •May have beta cell preservation Saxagliptin CrCl<50‐  by 50% DDP‐4 inhibitor •Low risk of hypoglycemia Alogliptin CrCl<60‐  by 50%, <30‐  by 75% •Minimal reduction in A1c Linagliptin None

• by 25‐50% when NPO All insulin No specific adjustments, but cleared Insulin •Increased clearance with good products renally graft function (post‐txp) References: Endocrino Metab Clin N Am 35 (2007) 873-890 910

FSHP 54th Annual Meeting – August 7-9, 2020 Oral Antidiabetic Agents in Transplant Post‐Transplant Hypertension Class Drug Renal Adjustments Comments • Incidence: 50‐90% eGFR 30‐45: not recommended for initiation of therapy • Etiology: • eGFR falls to <45 during therapy, consider •Rarely used: risk lactic • Native‐kidney mediated Biguanides Metformin benefits/risks of continuing therapy or dose acidosis, GI side effects • Donor‐kidney mediated reduction (eg, 50% reduction or 50% of maximal dose) • Renal artery stenosis eGFR <30: use CI • Drug‐induced Glipizide No specific recs • Steroids‐ Overstimulation of mineralocorticoid receptorsleads to sodium and water retention 2nd generation Glimepiride Use with caution •Risk of hypoglycemia • inhibitors (cyclo>tacrolimus)‐ Vasoconstriction of the afferent renal arterioles and intrarenal vessels sulfonylureas Glyburide CrCl<60: use CI due to endothelin release • Chronic allograft dysfunction Alpha‐glucosidase Acarbose Not recommended SCr>2 mg/dL or CrCl <25 •GI side effects • inhibitors Miglitol CrCl<25: Not been studied Goal BP • JNC8: <140/90 mmHg Renal impairment: Not been studies/use with Repaglinide •Minor substrate of • 2017 ACC/AHA: <130/80 mmHg Meglitinide Analog caution Nateglinide CYP3A4 • KDOQI/KDIGO goal: <130/80 mmHg • Acceptable to have higher BP in immediate post‐transplant period to ensure adequate renal •Heart failure Pioglitazone allograft perfusion (<150s/90s) Thiazolidinediones None •Peripheral edema Rosiglitazone •Bone fractures References: 1. Campistol et al Nephrol Dial Transplant 2004;19(3):64‐66 2. Najeed et al Int J Cardiol 2011;152:4‐6 3. Fernando Transplantation 2015;99:1016‐1022 11 12

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Treatment of Post‐Transplant Managing Hemodynamics Hypertension in the Transplant Patient • Calcium channel blockers (CCBs) • Volume • Dihydropyridine (amlodipine, nifedipine) • Significant DDI with nicardipine and non‐dihydropyridine CCBs with CNIs & mTORs (Potent • Albumin is key in liver transplant patients. Especially when serum albumin is less CYP‐3A4 inhibitor) than 2.5 or less than 3 with significant interstitial fluid volume. • Verapamil > diltiazem • Safe intravenous choice is clevidipine. • Avoid rapid sodium shifts in liver transplant patients. • Agent of choice for CNI induced HTN: counteracts vaso‐constrictive effects of CNIs • 6meq/24hrs. Above that increases risk of central pontine myelinolysis • ADR: edema, constipation Hetastarch contraindicated in liver transplant- risks • ACEI/ARBs • Not used within first 1‐3 months after kidney transplant • Pressors • May be beneficial in renal protective effects (insufficient literature) • ADR: hyperkalemia, , elevations in SCr • Vasopressin • Beta blockers • Norepinephrine • Useful post MI, high CAD risk, SV tachycardia • Dopamine • ADR: hyperkalemia, glucose intolerance

References: 1. Fernando Transplantation 2015;99:1016‐1022 2. Dobrowolski et al Neth J Med 2014;72(5):258‐263 References: 13 14

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Management of Arrythmias Management of Arrythmias

• Sinus tachycardia • Dofetilide, Flecainide • Fix underlying cause. Hypotension, anemia, pain, fever, etc. • Significant issues with renal function • Beta-blockers • Watch hypomagnesemia and hyperkalemia • Metoprolol DOC Ventricular arrhythmias • Calcium-channel blockers • Fix underlying cause • Diltiazem DOC • Drugs that increase QTc • Atrial fibrillation • Tacrolimus, cyclosporine • Fix underlying cause • Azole antifungals • Fluid overload, hypovolemia, check central line placement • antibiotics • Antipsychotics • Rate control first • Anti-depressants • Rhythm control • Correct hypomagnesemia • Amiodarone • Infuse IV magnesium at 2 grams iv x 1 then 1gram over 2 hours, and repeat as needed. • Significant drug interaction with most immunosuppression • Risk vs. benefit of diuresis with loops. • Hepatotoxin, pulmonary toxin. • Add amiloride where possible. (watch serum potassium)

References: References: 15 16

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Sedation and Agitation Sedation and Agitation in the ICU in the ICU Anti-psychotics • Propofol • Benefits- short acting. Easy titration. Short half-life even in significant liver disease • Haloperidol • Risks- myoclonic movements. No pain relief • Lowers seizure threshold. Higher risk with liver transplant patients • Benzodiazepines • Tacrolimus, history of alcoholic liver disease, hepatic encephalopathy, hypocholesterolemia, and • Lorazepam hypomagnesemia all risk factors • Benefits- can lower seizure risk. May help in treatment of akithesias. Safe to use in liver failure. • QTc prolongation • Risks- can induce psychosis. Half-life 6-8 hours with normal kidney function. No pain relief • Tacrolimus, hypomagnesemia, azole antifungals, antidepressants, all risk factors • Midazolam • Benefits- quicker onset than lorazepam. Half-life 4-6 hours with normal liver function • Akathisia • Risks- higher risk of respiratory depression with opiates. Can induce psychosis. No pain relief • Steroids may be a risk factor • Dexmedetomidine • Atypical anti-psychotics lower risk • No good studies in transplant • Benefits- less delirium, can be used after extubation Quetiapine or risperidone are good alternatives. • Risks- hard to manage pain with this alone. Unsure of clearance in patients with significant liver and kidney dysfunction

References: References: 17 18

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FSHP 54th Annual Meeting – August 7-9, 2020 Causes of Sleep Depravation in the Transplant Patient ICU Psychosis Non-pharmacologic causes Pharmacologic causes • Sleep depravation • Obstructive sleep apnea • Steroids • Interrupted sleep • Restless leg syndrome • Psychosis, bad dreams, racing thoughts, • Non-REM sleep • Peripheral neuropathies insomnia, confusion • • Difficulty falling asleep Calcineurin-inhibitors • Noises • tacrolimus > cyclosporine • Obesity • Racing thoughts • Alarms, staff conversations, Visitor conversations • Historical insomnia • Headaches, tremors, confusion • Ventilators, ECMO, VADs, CRRT machines • Pain or cough • Anti-thymocyte globulin • Phones and alarms at the nurses station. • Temperature dis-regulation • • Difficulty breathing • Environmental services • Bad dreams • Anxiety and agitation

Reilly‐Spong Clin Transplant 2013;27(6):1‐20 References: 19 20

FSHP 54th Annual Meeting – August 7-9, 2020 Progressive Reversible Encephalopathy Sleep Depravation in Syndrome (PRES) Transplantation Diagnosis • Remove underlying cause if possible • Increased T1 and T2 signal flaring on MRI • Preferred treatments • White matter areas • Rozerem Risk factors • Temazepam • CNI‐association • LOT drug- glucuronidated. Preserved even in cirrhosis. • JC virus (polyoma virus) • Personal choice in liver transplant patients • over immunosuppression? • Zolpidem Symptoms • If worked for patient in the past • Confusion • Hallucinations and sleep activities- could appear to be agitation • Expressive aphasia • Try to avoid frequent activities over night • Mutism • Reset sleep-wake cycle • Coma (severe cases)

References: 21 22

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Bacterial Infections Immunology of Sepsis in Transplant • Choose bacteriocidal drugs • Consider drugs that have a rapid reduction in endotoxin load • Aminoglycosides • Carbapenems • Cefepime • Quinolones • Combination therapy • Beta-lactam plus Aminoglycoside short course • Target good peak within 48 hours • First dose • Peak with first dose. Dose/Peak= Vd • High dose aminoglycosides (5-7mg/kg q24-48hours) • Good in heart, lung, and kidney transplant • Liver transplant patients may have very large Vd

References: Sriskandan et al J Pathol 2008;214:211‐223 References: 23 24

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th FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54 Annual Meeting – August 7-9, 2020 Effect of Antibiotics on Lipopolysaccharides Early Fungal Infection Risk Factors from Gram Negative Bacteria in Liver Transplantation • Pre‐transplant or post‐transplant renal failure • Large blood product use • Re‐operation • Bile leak • Bleeding • Delayed connection of bile duct • Patient left open after transplant‐back for closure • Primary non‐function • Hepatic artery • Long OR time; greater than 8 hours • Roux‐en‐y biliary anastomosis • Steroids Prophylaxis • Fluconazole 200mgs PO/IV daily 2 to 4 weeks ( 7 days TGH protocol) • Micafungin 100mgs IV daily x 7 days (TGH protocol)

References: Trautmann et al J of Antimicrobial Chemotherapy 1998;41:163‐169 References: 25 26

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Common Fungal Infections Common Fungal Infections in Lung Transplant in Lung Transplant • Thrush • Aspergillus spp. • Risk factor: high dose steroids (any organ transplant) • Site: most commonly occurs in lungs and sinuses, can cause disseminated • Clotrimazole 10mg PO QID after meals infections • Potent CYP 3A4/5 inhibitor • • Nystatin 100,000 units (5mL) swish/swallow QID after meals Diagnosis: radiographic findings, fungal cultures • • Candida Risk factors • • Single lung transplant recipients, early airway ischemia, CMV infections, increased net Respiratory tract (BAL): rarely indication of invasive candidiasis, typically not treated immunosuppression, Pre‐ or Post‐ transplant colonization, hypogammaglobinemia • Exception: anastomotic tracheobronchitis (anastomotic site) • Colonization increases risk of invasive infection 11 fold • Treatment: fluconazole 200‐400mg PO daily • Duration: at least ~14 days, until anastamosis clears • Prophylaxis • Highest risk within 30 days, infrequent due to common practice of aspergillus • Inhaled amphotericin deoxycholate and lipid formulations (complex/liposomal) prophylaxis • Unequal distribution in single lung transplant recipients • Risk factors: broad spectrum antibiotics, central venous catheters, CRRT • Systemic: , itraconazole

References: Am J Transpl 2004; 4(suppl 10): 110‐134. References: Am J Transpl 2004; 4(suppl 10): 110‐134 27 28

FSHP 54th Annual Meeting – August 7-9, 2020 Aspergillus Treatment in Transplantation Treating Rejection

Voriconazole* Dosing ADR/Comments

First line therapy IV: LD 6mg/kg q12hrx1 Voriconazole Target trough levels 2‐4 ug/mL day; MD 4mg/kg q12hr (IV,tablets) Major cyp3A4 inhibitor PO: 200mg q12h QTc prolongation

Amphotericin B (IV) IV: 3‐5mg/kg/day Nephrotoxic •Liposomal (ambisome) IV: 5mg/kg/day Elyte wasting: Ca,Ph,K •Lipd complex (abelcet) Casopfungin (IV) IV: 70mg day 1; 50mg/day Salvage therapy Micafungin (IV) IV: 100‐150mg qday Alternative therapy Solution PO: 200mg QID; then 400mg BID Major cyp3A4 inhibitor, QTc Posaconazole Tablet: 300mg PO BID day1, followed by 200mg PO prolongation (tablet, solution) daily Mild cases Itraconazole * OptimalPO: duration 200mg PO not TID defined.x 3 days; RecommendationsCapsules minimum≠solution 6-12 weeks (tablets, solution) then 200mg PO BID QTc prolongation with resolution/stabilization of clinical and radiologicMajor Cyp manifestations 3A4 inhibitor Isovuconazole IV/PO LD: 372mg PO q8h x 6 doses followed by Moderate Cyp 3A4 inhibitor (IV, tablets) IV/PO MD: 372mg PO daily

References: 29 30

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Categories of Immunosuppressive Agents Types of Rejection Hyper‐acute Acute Chronic Humoral Anti‐thymocyte globulin Alemtuzumab • Occurs within •Days to months •Months to •Days to months Induction Steroids minutes of after transplant years after after transplant transplant •T‐cells and transplant •Often occurs in • Clotting of graft macrophages •Multifactoral conjunction Rejection vasculature cause and not well with acute Steroids Treatment Increased maintenance •Many times of graft vessels understood rejection Alemtuzumab Maintenance Steroids leads to graft •Different name •B‐cells activate Anti‐thymocyte globulin Calcineurin Inhibitors loss and need for each organ: and lead to / Monoclonal for re‐ CAV, BOS, CAN, IVIG & Plasmapharesis Mycophenolate transplant VBDS activation

References: References: 31 32

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Acute Cellular Rejection Overview of Rejection

• Infiltration of the allograft by and other inflammatory cells • Signs/symptoms • Low grade fevers (?) • Pain over graft site (?) • Renal dysfunction (decreased UOP, increased SCr, etc) • Decreased PFTs • Increased T. Bili and Alk phos. Mild Increase in AST/ALT • Hearts‐ usually via biopsy • Hemodynamic instability predicts severe rejection • Increases risk of chronic rejection and allograft loss

References: References: 33 34

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Cellular Rejection Heart Transplant Cellular Rejection: in Kidney Transplant Diagnosis and Grading Banff ‘15 Acute cellular rejection • Grading based on histological findings on biopsy • 0R: No evidence of rejection • 1R: Mild acute rejection • 2R: Moderate acute rejection Type Histopathologic findings (biopsy) • 3R: Severe acute rejection (grade) • Any grade with ↓ EF or s/sx IA Interstitial infiltration and moderate tubulitis • Treated as 3R IB Significant interstitial infiltration and severe tubulitis IIA Mild to moderate intimal arteritis • Treatment options IIB Severe intimal arteritis >25% of luminal area • Supportive care for moderate to severe rejections Transmural arteritis and/or arterial fibrinoid change and necrosis of smooth • Increased baseline immunosuppression III muscle cells • PO vs. IV steroids; thymoglobulin

References: References: Rev Bras Cir Cardiovasc vol.26 no.2, 2011 35 36

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Cellular Rejection Cellular Rejection in Liver Transplantation Lung Transplant • Spirometry • 60% sensitivity for rejection or infection • Surveillance bronchoscopies • Transbronchial tissue biopsies: gold standard for diagnosis • Incidence • ~35-50% by 1 year (>A2) • Treatment • Inconsistent data of whether to treat A1 • > Grade A2: consensus of steroid pulse • ~20-40% can be asymptomatic • Methylprednisolone IV 500-1000 mg x 3 doses • Grade 3 or higher or steroid resistant • Antithymocyte immune globulin (thymoglobulin)

References: BANFF criteria for acute rejection in liver transplantation References: 37 38

FSHP 54th Annual Meeting – August 7-9, 2020 Treating Acute High‐Dose Corticosteroids Cellular Rejection • 500‐1000 mg of methylprednisolone IV at time of • High dose steroids transplant • depleting antibodies Dosing/Administration • Dosing varied amongst organs • Tapered over time • Anti-thymocyte globulin- rabbit •Used as both induction and maintenance • Alemtuzumab • and IVIG

• Increasing tacrolimus troughs •Converted to PO when patient tolerating PO • Steroid recycles •5 mg prednisone = 4 mg of methylprednisolone (IV and PO) • 40mgs daily, taper by 10mgs every few days. Pearls •Can be timed to be given as pre‐medication for Thymoglobulin

References: 39 40

Anti‐Thymocyte Globulin (Thymoglobulin®) Alemtuzumab (Campath®)

•1.5 mg/kg daily for 3‐5 days Dosing/Administration •Total thymoglobulin average dose: 4.5‐6 mg/kg Dosing/Administration •30 mg IV x 1 dose only •Central line administration preferred

• Reduce by 50%: WBC 2k‐3k cells/mm3 or PLT 50k‐75k cells/mm3 Dose Adjustments •Hold doses: WBC count <2k cells/mm3 or PLT<50k cells/mm3 •Cytokine release syndrome: fever, chills, hypotention, ARDS,. tachycardia, anaphylaxis •Premedication is Solu‐Medrol 500mgs intra‐op. Adverse Effects • and thrombocytopenia •CD4+ cell recovery at 1 year is 25‐50% •Cytokine release syndrome: fever, chills, tachycardia, anaphylaxis •Infections Adverse Effects •Pre‐medicate with steroids, APAP, and diphenhydramine •Increased infections and PTLD

41 42

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Mammalian Target of Rapamycin Calcineurin Inhibitors (CNI) Inhibitors (mTOR)

Drug Dosing Drug Side effects Interactions mTOR Dosing Drug Adverse Effects Interactions Sandimmune™ 5-7mg/kg po Nephrotoxicity (Cyclosporine) daily in 2 Neurotoxicity 1-3mgs po daily CYP-3A4/5 Impaired wound divided doses HTN, hyperlipidemia, Sirolimus Target levels 5- inhibitors and healing, CYP 3A4/5 ® diabetes, HUS (Rapamune®) 15mcg/ml inducers Lymphoceles Inhibitors and Low magnesium, Pneumonitis, Neoral™ Intravenous 1- inducers increased potassium (0.5mg, 1mg, PGP inhibitors Hyperlipidemia, (Cyclosporine 3mg/kg daily in Hepatotoxicity 2mg, liquid) and inducers Proteinuria, Modified) 2 divided doses PGP inhibitors Gingival hyperplasia, Arthralgias, rd hirsutism 1/3 of oral and inducers 0.75-1.5mgs PO Steroids Edema, Aphthous dose Everolimus BID Ulcers, Bone Drug levels Nephrotoxicity (Zortress®) Target levels 3- Bone marrow marrow Nephrotoxins Neurotoxicity 8mcg/ml Prograf™ 0-6mths 8- suppressants suppression, HTN, diabetes (0.25mg, (Tacrolimus) 15ng/ml Hepatotoxicity Anemia, leucopenia 0.5mg, Diabetes > 6mths 4- Low magnesium, 0.75mg) 8ng/ml* increased potassium Alopecia, HUS

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Pathophysiology of Antibody Mediated Rejection (AMR) Antibody Mediated Rejection • Often occurs in conjunction with acute cellular rejection • More common in patients with sensitization prior to transplant • Affects capillaries instead of myocytes • Diagnosed by presence of humoral markers • Presence of C4d on biopsy (byproduct of complement cascade) • Presence of circulating antibodies against transplanted heart • Treatment options • Plasmapheresis for 5 days • IVIG 0.5 –2 gm/kg • ± Bortezomib

45 J Heart Lung Transplant 2010;29(8):914‐956 Loupy. N Engl J Med 2018;379(12):1150‐60 45 46

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 AMR Targets Humoral Rejection (AMR)

• More common in highly sensitized patients • Evidence of (Banff ’15 AMR): • Acute tissue injury • Immunologic evidence of an antibody‐mediated process • Presence of C4d on biopsy (byproduct of complement cascade) • Circulating donor‐specific antibodies against kidney allograft • Treatment options • Plasmapheresis (PP) for 7 –14 days • IVIG 100 mg/kg after PP (total 1gm/kg) • ?Rituximab, ?bortezomib, ?, ?

References: Loupy. N Engl J Med 2018;379(12):1150‐60 References: 47 48

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Monitoring the Transplant Monitoring the Transplant Patient in the ICU Patient in the ICU • Drug levels • Neurologic exams • Troughs – Draw 30 minutes to 1 hour prior to administering dose. • Mental status changes • Infection vs Immunosuppression • CBC • Over-sedation • Daily- several drugs can cause • Hypo-perfusion • Hemodynamics • Malignancy • Vascular changes in CNS • Vitals when administering lymphocyte depleting antibodies. • Calcineurin receptors – memory and concentration • Q15 minutes x 1 hour, q30minutes x 1 hour, then q1hr. • Acute agitation • O2 Sats- especially in lung transplant patients • Gastrointestinal function • Chest X-ray • Constipation and diarrhea common from immunosuppression • Before administering Lymphocyte depleting antibodies • CMV colitis • Daily- look for ARDS, look for development of typical or atypical pneumonias • C Difficile

References: References: 49 50

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Monitoring the Transplant Kidney Transplant Patient in the ICU Chronic Rejection (IFTA) • Renal function • IFTA: interstitial fibrosis/tubular atrophy • Rapid changes in both directions • Formerly known as CAN (chronic allograft nephropathy) • BUN/SCr • UOP!!!! • Onset: months to years • U/A • Pathophysiology: combination of injury to graft from immune • Proteinuria, glucosuria, WBC, RBC, response, medications, response to injury • Urine electrolytes • Pain over transplanted kidney • Banff ‘15 Chronic Rejection Grading • Pulmonary function Grade Histopathalogic findings (biopsy) • Lung transplant patients – daily PFTs I (mild) Mild IFTA (<25% of cortical area) • Sign of infection vs rejection II (moderate) Moderate IFTA (25‐50% of cortical area) III (severe) Severe IFTA (>50% of cortical area)

References: References: 51 52

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Chronic Rejection: Chronic Rejection (IFTA) Coronary Artery Vasculopathy • Cardiac vasculature intimal proliferation • Multifactorial; poorly understood • Monitoring • Left heart catheterization • Intravascular ultrasound (IVUS) • Treatment • Prevention! • Stents, angioplasty, re‐transplantation Other primary Left Main Graft dysfunction vessels

CAV1 (mild) <50% <70% ‐‐

CAV2 (moderate) ≤50% ≥70% ‐‐

CAV3 (severe) ≥50% ≥70% ++ References: Davis, C. Am J Kidney Dis. 43(6),2004:1116‐1134 References: J of Heart and Lung Transplant 2010'; 29:717‐727 53 54

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Humoral Rejection in Humoral Rejection in Liver Transplantation Liver Transplantation Privileged organ Chronic Rejection • Contains a lot of immune cells • NK cells • Fairly rare complication • Dendritic cells • Endothelial cells • Vanishing bile duct syndrome • Kupffer cells • Stellate cells • Late hepatic artery thrombosis • Produces high levels of anti‐inflammatory cytokines • Donor artery • TGF‐beta, IL‐10 • Increases CD8 regulatory T‐lymphocyte activity • Recurrent cirrhosis • Donor specific antibodies (DSA) • Portal vein inflammation • Don’t see increased C4d positive deposition in liver tissue in acute AMR • Ischemic cholangiopathy may occur with high DSA • Increased risk with HCV patients

References: References: 55 56

Plasma Exchange (Plasmapharesis) Intravenous Immune Globulin (IVIG)

• Removal of antibodies from circulation • Derived from plasma pooled from blood donors • Albumin generally utilized as replacement • Primarily composed of IgG • Plasma exchange vs. immunoadsorption • Several proposed mechanisms of action • Limitations • Dose: 100 mg/kg x5‐7 doses  2 g/kg x1 dose • Bleeding risk from removing clotting factors • Limitations • Monitor fibrinogen • Transient and moderate reduction in DSA • Removes protein bound medications • Acute kidney injury risk with sucrose‐containing • Infection risk products • Rebound of antibody levels • Risk for infusion‐related reactions • Risk for aseptic meningitis

57 Levine M. Semin Immunol 2012;24(2):136‐142 58 Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanism of Action. Available at: https://www.researchgate.net/figure/Schematic‐ Levine M. Semin Immunol 2012;24(2):136‐142 representation‐of‐proposed‐mechanisms‐of‐action‐of‐IVIg‐in‐autoimmune‐and_fig1_6454825. Accessed April 20, 2020. 57 58

Rituximab (Rituxan®) Potential Targets in B‐Cell Lineage

• Anti‐CD20 that causes profound depletion in B cells • Dose: 375 mg/m2 weekly x1‐2 doses • Limitations • Only binds to CD20+ B cells • Infusion related reactions CD19 • Risk for infection CD20 • Conflicting literature CD22

Rituximab 59 60 Whittam D. Pract Neurol 2019;19:5‐20 Schrezenmeier E. J Am Soc Nephrol 2018;29(3):741‐758 59 60

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Factors Impacting Pharmacokinetics Treatment for BOS of Immunosuppression • Immunosuppression • Decreased Absorption • Azathioprine sirolimus • Drugs that affect CNIs and mTORs • Cyclosporine tacrolimus • Sucralfate, Magnesium oxide, Cholestyramine • Switch or addition of mTOR inhibitor • Drugs that affect Mycophenolic Acid derivatives • Alemtuzumab 30mg IV x 1 • PPIs – decrease mycophenolate mofetil absorption • Azithromycin • Oral iron- • 250mg PO every MWF • Decreased metabolism • Early stage treatment (before BOS2)  decreased risk of death • Diarrhea1 • Management • Sloughing of GI mucosa leads to decreased PGP-proteins • Prevention and early identification • Shunting of drug to the lower intestinal tract • Routine screening (spirometry) • Increased absorption of tacrolimus, cyclosporine, everolimus, sirolimus • Goal to halt progression, cannot reverse • CYP 3A concentrations are less lower in the GI tract

References: References: 1. Hochleitner et al Transpl Int 2001;14:230‐233 61 62

FSHP 54th Annual Meeting – August 7-9, 2020 Influence or Cytokines on Cytokine Effect on Immunosuppression Pharmacokinetics CYP Expression

CYP 3A4 Expression and Cytokines PGP expression and Cytokines

Liptrott et al Brit Journ Pharmacol 2009 156:497‐508 References: Aitken et al Drug Metab and Dispos 2007 35:1687‐1693 63 64

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Ethnic Differences in CYP 3A4 Expression Tacrolimus and CYP3A5

References: Krishna et al Methods Find Exp Clin Pharmacol 2005 27(8):559‐567 References: Jacobson P. Transplantation 2011;91:300‐308 65 66

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Drug Interactions TGH Recommended TDM Levels Cardiothoracic Tacrolimus Cyclosporine Sirolimus Everolimus 0 –3 months 10 –15 ng/mL 250 – 350 ng/mL ‐‐ ‐‐ 3 –6 months 8 –12 ng/mL 150 – 300 ng/mL 8 –12 ng/mL 6 –8 ng/mL > 6 months 6 – 10 ng/mL 150 – 250 ng/mL 4 –8 ng/mL 3 –6 ng/mL

Most frequent C0 every 2 –3 days weekly Abdominal Tacrolimus Cyclosporine Sirolimus Everolimus 0 –3 months 8 –10 ng/mL 200 – 300 ng/mL ‐‐ ‐‐ 3 –6 months 6 –9 ng/mL 100 – 250 ng/mL 8 –10 ng/mL 5 –7 ng/mL > 6 months 4– 6 ng/mL 75– 200 ng/mL 4 –8 ng/mL 3 –5 ng/mL FSHP 54th Annual Meeting Most frequent C0 every 2 –3 days weekly August 7-9, 2020 References: 67 68

Pharmacokinetic Drug Interactions Mycophenolate Drug Interactions

• CYP 3A4/5 substrates Drug Effect Comment Altered GI flora • Cyclosporine, tacrolimus, sirolimus and everolimus Disrupts enterohepatic circulation (cholestyramine/ Avoid ( MPA by 40%) CYP 3A4 Inhibitors CYP 3A4 Inducers PO antibiotics) ( ↑ concentraons) ( ↓ Concentrations) Antacids (Al/Mg)  Absorption Separate by 2h Rifampin/Rifabutin Iron  Absorption Separate by 2h Ex: clarithromycin, erythromycin, azithromycin Acyclovir Anticonvulsants Compete for renal tubular secretion  levels Conflicting data Azole Antifungals Ganciclovir Ex: Carbamazepine, phenobarbital, Inhibit renal tubular secretion Ex: fluconazole, voriconazole, posaconazole Probenecid  Dose phenytoin  levels Calcium Channel Blockers Cyclosporine  MPA trough and AUC  Dose Verapamil, diltiazem, nifedipine St. John’s Wort Others: Protease inhibitors, metoclopramide, amiodarone, cimetidine, grapefruit juice

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Drug Interactions: Impact of CYP Inhibitors Drug Interactions: Impact of CYP Inducers

Tacrolimus Cyclosporine Sirolimus Everolimus Corticosteroids Fluconazole ↑↑ ↑↑ ↑↑ ↑↑ ↑ Tacrolimus Cyclosporine Sirolimus Everolimus Corticosteroids Voriconazole ↑↑ ↑↑ ↑↑ ↑↑ ↑ Oxcarbazepine ‐↓‐ ‐ ‐ Posaconazole ↑↑ ↑↑ ↑↑ ↑↑ ↑ Carbamazepine ↓↓ ↓↓ ↓↓ ↓↓ ↓ Itraconazole ↑↑ ↑↑ ↑↑ ↑↑ ↑ Phenytoin ↓↓↓↓↓↓↓↓ Erythromycin ↑↑↑ ↑↑ ↑↑ ↑↑ ↑ Phenobarbital ↓↓ ↓ ↓↓ ↓↓ ↓ Azithromycin ↑↑↑↑ ‐ Primidone ↓↓ ↓↓ ↓↓ ‐ ↓ Amlodipine ‐↑‐ ‐ ‐ Rifampin ↓↓ ↓↓ ↓↓ ↓↓ ↓ Nicardipine ↑↑ ↑↑ ↑ ↑↑ ‐ Rifabutin ↓↓ ↓↓ ↓↓ ↓ ↓ Diltiazem ↑↑ ↑↑ ↑↑ ↑↑ ↑ Efavirenz ↓↓ ↓↓ ↓↓ ↓↓ ‐ Amiodarone ↑↑ ↑↑ ↑↑ ↑↑ ‐ HIV Protease Inhibitors ↑↑ ↑↑ ↑↑ ↑↑ ↑

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FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Take Home Message for CYP-450 Immunosuppression: Alternative Inducers and Inhibitors Routes of Administration • Calcineurin-Inhibitors • Half life may determine peak onset and cessation of interaction • Tacrolimus • Shorter half-life quicker on and off • Sublingual- preferred vs IV • Check levels about 3 to 5 days after start and stop CYP drugs Dose is 50% of oral dose to start • Via GT or FT • Need to repeat with long acting drugs in 3 to 5 days • Intravenously • Inducers take longer to begin • IV dose is ¼ oral dose- infused over 24 hours • Need to make new proteins • Cyclosporine • Liquid Via GT or FT commercially available • IV dose is 1/3rd or oral dose

References: References: 73 74

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 CNIs via Oral Tubes Why Sublingual? • Both drugs are big, bulky, plastic-loving molecules – which means the tubing will get more of the drug than the patient in the first few days • Used when: …but eventually the tubing will be saturated • Patient is unable to swallow • Strict NPO due to pancreatitis, high aspiration risk, NG to continuous suction, etc • Sublingual is preferred over via tube administration for tacrolimus • Significant nausea/vomiting • Open capsules vs. compounded liquid? • Intubated immediately post-operatively • Poor absorption • Cyclosporine modified commercially available liquid • When patients need higher and higher doses to achieve adequate levels (African Americans, young people, cystic fibrosis, etc) • Avoidance of interaction between tacrolimus and food (lung transplants) • IV is undesirable • Cost • Need for continuous infusion via dedicated line • Increased adverse effects

References: References: 75 76

FSHP 54th Annual Meeting – August 7-9, 2020 FSHP 54th Annual Meeting – August 7-9, 2020 Tacrolimus Sublingual Immunosuppression Alternative Administration Routes of Administration 1. Mask and Glove up! • Mycophenolate Derivatives • Myfortic 360mg = Cellcept 500mgs 2. Hold capsule upright, and tap contents to one end • Myfortic only available in tablets 3. Remove the top, empty portion of the capsule • Cellcept comes in a commercial liquid • Cellcept comes intravenously 4. Deposit capsule contents for total dose in to plastic spoon • 1:1 oral to IV conversion • Separate designated line for infusion. 5. Hold the powder under tongue • Prepared before administration • Conscious Patients: instruct not to swallow powder • 2 hour infusion. Short stability ~4-6hrs • Unconscious Patients: attempt to limit excessive saliva/involuntary swallowing • mTORs 6. Allow all powder to completely dissolve (30 minutes) before food, • Everolimus oral only • Sirolimus oral or liquid. liquids, or suctioning (if possible) • No good conversion between the two drugs.

References: References: 77 78

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FSHP 54th Annual Meeting – August 7-9, 2020

Critical Keys to Managing the Transplant Patient in the ICU Drew Silverman, Pharm.D; Pharmacotherapy Specialist in Abdominal Transplantation; Tampa General Hospital th FSHP 54 Annual Meeting [email protected] August 7-9, 2020 79

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