- Tacrolimus is an immunosuppressant commonly used to prevent organ rejection after transplantation. It works by inhibiting T cell activation through blocking calcineurin. - The standard dosage varies depending on the organ transplanted and is monitored through drug level testing. Factors like CYP3A5 and MDR1 gene polymorphisms can impact drug levels. - Studies have found tacrolimus monotherapy can effectively prevent rejection in kidney transplant with fewer side effects than prednisone. It has also shown benefits after liver and lung transplantation. Prolonged release formulations have demonstrated good adherence and outcomes.

1. Role of Tacrolimus in
Transplantation

2. Overview of Transplant
• Transplantation is the removal of living, functioning cells, tissues, or organs (solid organ
transplants) from the body and transfer back into the same body or into a different body.
• Transplant consist of,
• Tissues (own tissues, issues from an identical twin or non-identical individuals or different species)
• Cells (stem cell)
• Partial organ (Lung, Bowel and Liver etc)
• Entire organ (Heart, Kidney etc)
• Composite transplants (> one tissue)
• Process:
• Transplant Donors
• Organ Matching and Distribution
• Pre-transplantation Screening
• Suppression of the Immune System
• Post Transplantation complications prevention and management
MSD MANUAL Consumer Version Jun 2020since 1899

3. Transplant Matching System
PPT - Transplantation: Mechanisms of Tacrolimus PowerPoint Presentation - ID:2072512 (slideserve.com)

4. What happened during a transplant
• Immune response and organ rejection
• MHC class I molecules=cell surface recognition
• Highly polymorphic
• Recognition of polypeptide by T cells
• Multiple mechanism of rejection
• Direct pathway
• Indirect pathway

5. Direct Pathway
• Acute graft rejection
• Recognition of self Vs non self
• T cell recognize alloantigens
• T cell stimulated by APCs from donor
• T cell Activation and proliferation
Immunobiology: The Immune System in Health and Disease. 5th edition. https://www.ncbi.nlm.nih.gov/books/NBK27163/

6. Indirect Pathway
• T cell recognize foreign antigens from donor
• Recipient APCs present these antigens
• Lead to proliferation
Immunobiology: The Immune System in Health and Disease. 5th edition. https://www.ncbi.nlm.nih.gov/books/NBK27163/

7. T cell activation
 Increase intracellular Calcium
 Calcineurin dephosphorylates NFAT
 IL-2 upregulated
Immunobiology: The Immune System in Health and Disease. 5th edition. https://www.ncbi.nlm.nih.gov/books/NBK27163/

8. How to prevent organ rejection
• Before transplantation
• Recipient and donor compatible blood types
• Genetic compatible matching
• Mostly relative preferred for living donor
• Post transplantation
• Frequent monitoring of Lab results during the first year after transplant
• Anti-rejection medications;
• Immunophilin-binding agents/Calcineurin inhibitors (Tacrolimusand Cyclosporine)
• mTOR inhibitors
• Antiproliferative agents
• Antibodies
• Corticosteroids
• Educate receipt for the possible signs of organ rejection
Preventing Organ and Tissue Rejection 2020 https://www.donoralliance.org/newsroom/donation-essentials/preventing-organ-and-tissue-rejection/?cli_action=1626768576.138

9. Tacrolimus as immunosuppressant therapy in
Transplant
 Calcineurin-inhibitor immunosuppressant
 FDA primarily approved in 1994 for transplant
 Clinical use as prophylaxis of organ rejection in allogeneic
liver, kidney or heart transplants
 Approved use as concomitant with adrenal corticosteroids
and conjunction with azathioprine or mycophenolate mofetil
for kidney and heart transplant
Tacrolimus prescribing information Reference ID: 3083402
Synonymes: FK-506, Streptomyces sp. - CAS 104987-11-3 - Calbiochem

10. Mechanism of Action Tacrolimus
 Prevent dephosphorylation of NAFTc
 Block NAFTc transport to nucleus (NAFTn)
 Prevent IL-2 production
 Prevent T cell Activation
 Immunosuppression
 Prevent Organ Rejection
Mechanism of action of tacrolimus (FK506)
Tacrolimus (FK506) + immunophilin FK506‐binding protein
(FKBP
FK506 and FKBP Complex
Enzyme Calcineurin (CaN)

11. Tacrolimus Dosage
Tacrolimus prescribing information Reference ID: 3083402
Dosage in Pediatric Liver Transplant

12. Tacrolimus level assay
• Methods commonly use are,
• Liquid chromatography with tandem mass spectrometric detection
(HPLC/MS/MS) 
• Mass spectrometry (MS)
• Chemiluminescence
• Immunoassays
• Enzyme-linked immunosorbent assay (ELISA)
• Microparticle enzyme immunoassay (MEIA)
• Second generation Microparticle enzyme immunoassay (MEIA II)
 widely use method for tacrolimus therapeutic level monitoring
Ann Clin Biochem 1998; 35: 167-180 Therapeutic monitoring of tacrolimus

13. Effectiveness of Tacrolimus Monotherapy
 Relapse rate reported in prednisolone group (17 out of 23) [74%] and in tacrolimus group (16 out of 22) [72%]
 Tacrolimus monotherapy can be effective alternative treatment for steroid sparing De Novo Minimal Change
Disease
Randomized, Controlled Trial of Tacrolimus and Prednisolone Monotherapy for Adults with De Novo Minimal Change Disease CJASN February 2020, 15 (2) 209-218; DOI: https://doi.org/10.2215/CJN.06180519

14. ATHENA study- Everolimus with Tacrolimus or
Cyclosporine
C Sommerer et al.: Everolimus in kidney transplantation

15. Pharmacogenomic Effect-MDR1 and CYP3A5 Gene
Polymorphism on Tacrolimus in Renal Transplant
• CYP3A5 genotype polymorphisms lower
the TAC level
• CYP3A5 and MDR1 G2677T/A genotype
required the highest daily TAC dose to
maintain target trough level of TAC
• Homozygous mutant SNP of G2677A/T
requires a higher dose than the
heterozygous and wild-type genotypes
• Wild-type (GG of G2677T/A) genotype
requires lowest dose
N Prasad et al.: MDR1 and CYP3A5 Gene Polymorphism on Tacrolimus
CYP gene and MDR1 gene polymorphisms affect the TAC dose required to achieve the target trough concentration

16. New Entrant Tracrolimus therapy: VIGILung—
study
Gottlieb et al. Trials (2021) 22:48
• High-dose calcineurin inhibitors (CNI) is essential
after lung transplantation
• Adaptation of CNI-based immunosuppression by
monitoring of torque teno virus (TTV), a latent
nonpathogenic DNA virus in addition to
conventional therapeutic drug monitoring may
reduce the toxicity of immunosuppression with
similar efficacy

17. Adherence and tolerability of prolonged-
release tacrolimus
FIGURE 1 Evaluation of individual BAASIS components. BAASIS, Basel
Assessment of Adherence with Immunosuppressive Medication Scale
FIGURE 2 Mean creatinine clearance over time. SD, standard deviation; V, visit
• Once-daily prolonged-release tacrolimus formulation was associated with good clinical outcomes
• Satisfactory adherence found with renal transplant recipients taking the prolonged-release tacrolimus
formulation
• Long-term maintenance immunosuppression showed low adherence based on Basel Assessment of Adherence
with Immunosuppressive Medication Scale
LEHNER et al. Clinical Transplantation. 2018;32:e13142 DOI: 10.1111/ctr.13142

18. Protective Role of Tacrolimus in Liver Transplant
Recipients With Covid-19
 Older than 70 age Covid 19 liver transplant patients with tacrolimus (TAC) use was associated with a better
survival than non TAC user
 This study encouraging clinicians to keep TAC at the usual dose in oldage covid 19 liver transplant
patients
Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study December 08,
2020DOI:https://doi.org/10.1053/j.gastro.2020.11.045

19. Efficacy and safety of Tacrolimus Vs ciclosporin A
in renal transplantation
Fig. 3. The estimated combined endpoint-free survival rate (Kaplan–Meier method) at the
36-month follow-up using the ITT population was 71.4% with tacrolimus and 55.4% with
ciclosporin ME (P ≤ 0.001).
• Efficacy of tacrolimus was better at 36 months comparing with
ciclosporin A
• Significantly high estimated combined endpoint-free survival
rate (BPAR, graft loss and patient death)
• Tacrolimus use group had less hypercholesterolaemia with less
antihyperlipidaemic use
B. K. Kramer ¨ et al. Efficacy and safety of tacrolimus compared with ciclosporin A in renal transplantation

20. Thank You