Updates in Transplant Medication and Technology Alicia Lichvar, PharmD, MS, BCPS University of Illinois at Chicago Department of Pharmacy Practice and Surgery August 18th 2018

Disclosures I have no actual or potential conflict of interest in relation to this presentation

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

Anti-Rejection Medications: A Necessary Evil, A Force for Good

Immunosuppression– What’s YOUR regimen? Tacrolimus Cyclosporine Belatacept Mycophenolate Azathioprine Sirolimus/ Everolimus Steroids

Immunosuppression Regimens– Basically Spaghetti Sauce!

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

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%

Immunosuppression– the Real Heroes! Backbone agent Adjunctive agent Steroids (maybe) Prevent rejection

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

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

Seeking The Perfect Balance Toxicity Infection & Malignancy Rejection

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 15-20 years ago More infection? Long term benefit?

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

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

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.

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.

Strategies to improve adherence Ways we can help….. 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 Education regarding the value and necessity of anti-rejection medicines and what to do when issues arrise Clin Transplant 2012: 26: 706–713

What ways help you remember your medications?

Traditional Strategies Pillboxes Keeping medications in key locations in the house Traveling with medications– even if you’re gone for the afternoon! Phone alarms

Apps Medisafe Mango Health Round Health Care4Today CareZone MedPal MyMeds Mango Health Round Health JMIR 2017;5(4):e45

Medisafe https://medisafe.com/

Medisafe Comprehensive medication adherence tracker Measurement tracker Weight and waist circumference A1c and blood glucose Serum creatinine and eGFR (kidney numbers) Blood pressure And much more….. Option to add in your doctors and appointment reminders

Medisafe Am Heart J. 2017 Apr;186:40-47.

Mango Health https://www.mangohealth.com/

Mango Health Enter and track medications with alerts Health habit trackers Weight Food recording (not as good as other apps, but available) Blood pressure Blood sugar Mood

Mango Health https://www.npr.org/sections/health-shots/2014/10/17/354378494/take-your-medicine-tap-your-phone-and-collect-a-prize

Round Health

Round Health Medication and adherence tracking Sets a window to take medications that increase in notification intensity With a user account, can export and synch between devices Simple, easy, and limited to medication tracking

Other Non-medicine Apps MyFitnessPal Track steps, exercise, and other activities Record food intake and hydration Trend weight and body measurements Apple Health Tracks steps (with an Apple phone or watch) Record medication lists (not adherence) Document vital signs and lab values

Our Current Practice at UI Health: Paper!

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

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

Conclusions and Final Thoughts

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!

Updates in Transplant Medication Alicia Lichvar, PharmD, MS, BCPS University of Illinois at Chicago Department of Pharmacy Practice and Surgery April 14th 2018