Transcript Tobin Klinkhammer Pharm.D. Avera Transplant Institute Symposium March 27, 2014 Objectives Discuss the historical perspective of chemoimmunosuppression  Briefly describe basic advantages &/or disadvantages of current immunosuppressants 

Tobin Klinkhammer Pharm.D.
Avera Transplant Institute Symposium
March 27, 2014
Objectives
Discuss the historical perspective of
chemoimmunosuppression
 Briefly describe basic advantages &/or
disadvantages of current
immunosuppressants
 Discuss potential new agents or dosage
regimens for future anti-rejection
protocols

History Timeline
1902: First successful experimental
kidney transplant
 1906: First human kidney transplant –
xenograft
 1933: First human kidney transplant –
allograft
 1950s: Human kidney allografts without
immunosuppression

History
1959-62: Radiation used for
immunosuppression
 1960: 6-Mercaptopurine
 1962: Azathioprine
 1962-63: Prednisone/Prednisolone
 1978: Cyclosporine
 1987: Tacrolimus
 1990s: Multiple Immunosuppressants

Thiopurines

6-Mercaptopurine (6-MP)
 Anticancer agent
 Toxicity: High rates of infections leading to
death

Azathioprine (AZA)
 Derivative of 6-MP
 Multiple metabolic pathways and can be
converted back to 6-MP
 AZA & 6-MP require normal Thiopurine SMethyltransferase enzyme (TPMT)
Azathioprine

Never given a proper chance to succeed
 Improper dosing
 Poor immunosuppressive regimens
 Side effects (Bone Marrow Aplasia)

Largely replaced by Mycophenolate
 Less rejection but similar patient & graft
survival

Viable option
 Pregnancy & GI issues with Mycophenolate
Corticosteroids
Reverse acute rejection
 Added to Azathioprine as maintenance
therapy
 Multiple side effects

 Added cost to complications
Withdrawal and Avoidance Protocols
 Conflicting data

Cyclosporine
First Calcineurin Inhibitor (CNI)
 Allowed transplantation beyond renal
 Liver and Heart became routine
 Clinical trials in Pancreas and Lung

Tacrolimus
2nd Generation CNI
 First immunosuppressant to be
approved in Liver transplant vs. Kidney
 Rescue therapy
 Antibody-Mediated Rejection
 Small-bowel transplants

Calcineurin Inhibitors

Backbone Immunosuppressant
 Tacrolimus: Majority of Kidney & Liver patients
on at initial discharge
Corticosteroid Sparing
Drug Interactions
Narrow therapeutic window and drug
concentration monitoring
 Significant side effects



 Nephrotoxicity
 Coronary Artery Risk Factors
 Diabetes
Mycophenolate
50% reduction in acute rejection
compared to azathioprine
 Steroid and CNI dose reductions
 Mechanism more specific to
lymphocytes compared to neutrophils
 Gastrointestinal side effects

 Also hematological
CMV and BKV
 Pregnancy

Mammalian Target of Rapamycin
Inhibitors
Sirolimus and Everolimus
 Originally designed to replace CNI
 Anti-cancer effects
 Require drug concentration monitoring
 Similar drug-drug interactions as CNI
 Side effects

Biologics
Rejection rates in 1960s spurred interest
 Induction therapy

 83% kidney transplants
Growing in maintenance therapy
 Many are non-FDA approved indications
 Monoclonal vs. Polyclonal
 Depleting vs. non-depleting

Depleting Agents
Induction and Rejection
 Muromonab – removed from market
 Antithymocyte Globulin

 Only polyclonal antibody used in SOT
Alemtuzumab
 Rituximab
 Infectious and oncological risks

Basiliximab
Induction only
 Comparable efficacy to depleting agents
in low risk patients
 Favorable side effect profile

Belatacept
First biologic approved for maintenance
therapy
 Designed to replace CNI (CsA*)
 Higher GFR but more rejection
 Patient and graft survival similar.
 Corticosteroids?
 Viral Infections
 Must be EBV seropositive
 Improved compliance?

Future
New Compounds
 Existing Compounds with New
Indications
 New dosing strategies
 Treatment Adherence
 Safety and Tolerability
 Agents with Immunosuppressive and
Antiviral Properties

Clinicaltrials.gov
Excellent resource for active or recently
completed clinical trials
 Results are not always posted

New Compounds

ASKP1240
 Anti-CD40 monoclonal antibody.
 Maintenance therapy
 Studies in Plaque Psoriasis

Sotrastaurin
 Protein Kinase C inhibitor
 CNI-avoidance vs. Mycophenolate-
avoidance
New Indications - Biologics

Eculizumab
 Atypical Hemolytic Uremic Syndrome &
Paroxymal Nocturnal Hemoglobinuria
 Complement component of AMR

Autoimmune agents
 Mainly case reports
Enzyme Inhibitors

Bortezomib
 Multiple myeloma
 Antibody-mediated Rejection. Mixed results
 Induction?

Tofacitinib
 Rheumatoid Arthritis
 Higher dose
 Extended trial
Leflunomide &Malononitrilamides
Rheumatoid Arthritis
 Immunosuppressive and Antiviral
properties

 CMV & BKV

Human trials disappointing
New Dosing Strategies
Induction – dosing and frequency
changes
 SCD vs. ECD vs. DCD
 Different maintenance combinations
 Avoidance and Minimization Protocols
 Infectious Complications

Adherence
Single vs. Dual vs. Triple therapy
 Once daily options
 Monthly Injections

Safety & Tolerability
Rejection, Graft and Patient Survival
 Minimize Serious (and all) Side Effects
 Quality of Life

Different Strategies

Total Lymphoid Irradiation
 Require hematopoietic stem cell transplant
and ATG
 Cost

Apheresis
 Photopheresis – UVA light and methoxsalen
 Plasmapheresis – +/- IVIG and rituximab
&/or cyclophosphamide
○ Desensitization or Acute Humoral Rejection
Conclusions
Current medications and regimens
 Room for improvement
 Changing mindset
 Radical changes
 Individualized treatment

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