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Updates in Transplant Medication
Alicia Lichvar, PharmD, MS, BCPS University of Illinois at Chicago Department of Pharmacy Practice and Surgery April 14th 2018
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Disclosures I have no actual or potential conflict of interest in relation to this presentation
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Learning Objectives Discuss the current practices of transplant immunosuppression in the United States (US) for renal transplant recipients List different medications for transplant immunosuppression Review some of the updates for transplant medication
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Anti-Rejection Medications: A Necessary Evil, A Force for Good
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Immunosuppression– What’s YOUR regimen?
Tacrolimus Cyclosporine Belatacept Mycophenolate Azathioprine Sirolimus/ Everolimus Steroids
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Immunosuppression Regimens– Basically Spaghetti Sauce!
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Immunosuppression Types
Desensitization therapies (aka the “bells and whistles”) Induction therapies (aka “clearing the field”) Maintenance therapies (aka “tricking the body”) Rejection therapies (aka “factory reset”) REJECTION (if needed) DESENSITIZATION (if needed) TRANSPLANT TIME LINE INDUCTION MAINTENANCE
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Timeline Of Immunosuppression Therapies
Tacrolimus Mycophenolate mofetil Rituximab (CD20) Basiliximab (CD25) Daclizumab (CD25) Sirolimus Thymoglobulin Everolimus Belatacept Bortezomib Eculizumab XL and XR-Tacrolimus Graft survival at 1 year 50% 80% Azathioprine Steroids Cyclosporine 1950 1960 1970 1980 1990 2000 2010 2020 1954 – 1st LRT AZA – prodrug for mercaptopurine, 1957 PRED – marketed 1955 But not until 1962 first time used together (AZA-prednisone) for non identical allo-RT At same time, animal- antibodies against human T cells CSA – approved 1983 OKT3 1986 Irradiation Anti-T Cell Antibodies Atgam Muromonab (CD3) Alefacept Tofacitinib Alemtuzumab (CD52) Mycophenolate sodium Graft survival at 1 year 0% 30% Graft survival at 1 year 80% 90%
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Immunosuppression– the Real Heroes!
Backbone agent Adjunctive agent Steroids (maybe) Prevent rejection
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Immunosuppression– the Real Heroes!
Tacrolimus and cyclosporine Mycophenolate Backbone agent Adjunctive agent Steroids (maybe) Prevent rejection Sirolimus and everolimus Azathioprine Prednisone Belatacept Sirolimus and everolimus
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Maintenance IMS Toxicities
GI toxicity Anemia Leukopenia MPA Nephrotoxicity Neurotoxicity Hypertension Diabetes Hyperlipidemia Electrolyte disorders Hirsutism/Alopecia GI toxicity Gout CNIs Remember, immunosuppression works best when used in combination! Edema Anemia Hyperlipidemia Proteinuria Mouth ulcers Wound healing mTORi Osteoporosis Diabetes Weight gain Body changes Glaucoma Wound healing Steroids PTLD Infusion reactions Bela
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Seeking The Perfect Balance
Toxicity Infection & Malignancy Rejection
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Which Combination is Best?
Best IMS regimen is unknown 253 Transplant Centers in USA Every center has its own “best” protocol Less medications vs. less of each medication? Azathiprine + Predinsone Sirolimus + Mycophenolate + Prednisone Tacrolimus + Azathioprine + Prednisone Cyclosporine + Mycophenolate + Prednisone Tacrolimus + mycophenolate + Prednisone Sirolimus + Tacrolimus + Prednisone Cyclosporine + Mycophenolate Tacrolimus + Mycophenolate Less rejection compared to years ago More infection? Long term benefit?
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Optimizing Immunosuppression
Individualization of the drug regimen to the patient Things to think about…. Risk of rejection Expected or existing drug side effects Medication adherence Other chronic illnesses (i.e. high blood pressure, diabetes mellitus) Risk of infections
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Optimizing Our Current Medications
“Drugs don’t work in patients who don’t take them” - C. Everett Koop, MD ADHERENCE to medication regimen is more crucial then ever before At least 23% of transplant recipients don’t take their medications as prescribed
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Defining Medication Non-adherence
World Health Organization Classification of Risk Factors for Non-adherence Socioeconomic Age, gender, employment status, financial status, level of education Patient/ disease-related factors Health beliefs/ behaviors Treatment-related factors Patient symptoms, side effects of medications Healthcare system factors Lack of health insurance or health benefits Clin J Am Soc Nephrol 2010: 5; 1305–1311.
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Transplant-Specific Factors for Medication Non-adherence
Social/ Economic Related Medication/Therapy Related Patient Related Condition Related Health System/ Medical Care Related Younger patients Male gender Non-US resident Poor social support Poor transportation Poor literacy Complex medicine regimen Higher medication toxicity Lack of medication education No pillbox/ reminder system History of non-adherence Adolescence Psychological disorder Cognitive impairment Substance abuse Negative beliefs about medications High symptom distress Development of new onset diabetes mellitus Increased time post-transplant Medication costs Poor access to medications Poor aftercare planning Poor physician-patient relationship Poor physician-patient communication Am J Transplant. 2018;18:564–573.
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Transplant-Specific Factors for Medication Non-adherence
Social/ Economic Related Medication/Therapy Related Patient Related Condition Related Health System/ Medical Care Related Younger patients Male gender Non-US resident Poor social support Poor transportation Poor literacy Complex medicine regimen Higher medication toxicity Lack of medication education No pillbox/ reminder system History of non-adherence Adolescence Psychological disorder Cognitive impairment Substance abuse Negative beliefs about medications High symptom distress Development of new onset diabetes mellitus Increased time post-transplant Medication costs Poor access to medications Poor aftercare planning Poor physician-patient relationship Poor physician-patient communication Am J Transplant. 2018;18:564–573.
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Things Patient’s Think about When They Think about Their (Transplant) Medicines
Empowerment Fear of consequences Managing regimen demands Overmedicalizing life Social accountability and motivation Am J Transplant. 2018;18:564–573.
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Ways we can help and how patients can help themselves…
Clin Transplant 2012: 26: 706–713
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Ways we can help and how patients can help themselves…
Strategies to improve adherence Develop system of reminder cures Involve family members and/or friends as support system Simplify immunosuppression medication regimen (as much as possible) Work to improve adherence when daily routines are upset Verbal and written education regarding the value and necessity of anti-rejection medicines in maintenance of the transplanted organs and patient health Clin Transplant 2012: 26: 706–713
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What ways help you remember your medications?
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Apps Medisafe Mango Health
Care4Today CareZone MedPal MyMeds Mango Health JMIR 2017;5(4):e45
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Medisafe
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Medisafe Am Heart J. 2017 Apr;186:40-47.
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Mango Health
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Mango Health
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Our Current Practice at UI Health: Paper!
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Other Services We Utilize
Medication Therapy Management (MTM) Clinic Pharmacist run clinic Spend dedicated time with select transplant patients Provide additional education, fill pillboxes, and help manage refills Medication Assistance Program Part of the UI Health Wood Street Pharmacy Help patients in financial need obtain medication vouchers and other forms of patient assistance
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Our Approach: Attack from all sides
Re-establishing a new routine Medication adherence Financial assistance Patient and family education Support system of doctors, nurses, social workers, and pharmacists
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Timing is Everything When It Comes to Tacrolimus
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Tacrolimus Levels– Why do I care so much?
Levels can be too high Increase side effects when we give more than we need Levels can be too low Increase risk for rejection and other bad things Levels can be variable That’s bad too!
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Tacrolimus Levels– Why do I care so much?
New data published stresses the importance of being consistent with medication timing Timing is everything when it comes to taking your transplant medicine!
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Erratic Tacrolimus Levels = BAD!
Tacrolimus level stable Erratic tacrolimus levels = BAD! Increased risk of losing the kidney! Increased risk of developing antibodies to the kidney! Tacrolimus level variable Rodrigo E. Transplantation. 2016;100(11):
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Erratic Tacrolimus Levels = BAD!
Mean CV% = 9.8 ± ± ± 7.8 Change in Chronic Histologic Score from 3 months to 2 years When biopsied– more kidneys had chronic scarring and fibrosis Chronic scarring and fibrosis Linked with kidney transplant failure
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Erratic Tacrolimus Levels = BAD!
Higher risk Late outcomes: Graft failure, late rejection and transplant glomerulopathy (kidney scaring), or increased kidney numbers Worse late outcomes when Tacrolimus levels were “low” Tacrolimus levels were “erratic” ERRATIC tacrolimus levels Higher risk LOW tacrolimus levels Transplant International 2016;29:
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Time “In Range” Matters for Tacrolimus
Am J Transplant. 2018;18:907–915.
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Time “In Range” Matters for Tacrolimus
MORE REJECTION! (BAD) LOSE THE KIDNEY! (WORSE) Am J Transplant. 2018;18:907–915.
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What about the others? Transplant medications requiring blood level monitoring Tacrolimus (Prograf, Astagraf, and Envarsus) Cyclosporine Sirolimus Everolimus Mycophenolate (Myfortic and Cellcept)
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Conclusions and Final Thoughts
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Conclusions Much of the current literature being investigated in transplant relates to medication adherence Adherence to medication is an important factor for transplants to maximize their lifespan and to avoid complications The best approach to optimize medication adherence with teaming up with your healthcare team to find a customized strategy that works for you!
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Updates in Transplant Medication
Alicia Lichvar, PharmD, MS, BCPS University of Illinois at Chicago Department of Pharmacy Practice and Surgery April 14th 2018
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