The Calcineurin Inhibitors Ciclosporin and Tacrolimus

Harefield Hospital, Royal Brompton and Harefield NHS Trust, Harefield, Middx, UB9 6JH, UK

[email protected]

1 Introduction 322

2 The Alloimmune Response and Allograft Rejection 323

3 Discovery of Ciclosporin and Tacrolimus 327

4 Structure and Binding to the Immunophilins 328

5 Mechanism of Action 328

6 Clinical Use of the Calcineurin Inhibitors 331

6.1 Transplantation 331

6.1.1 Maintenance Immunosuppression 331

6.1.2 Treatment of Acute Rejection 332

6.1.3 Rescue Therapy 333

6.1.4 Hyperacute and Chronic Rejection 333

6.1.5 Current Practice 333

6.2 Allogeneic Bone Marrow Transplantation 334

6.3 Indications Other than Organ Transplantation 334

6.3.1 Nephrotic Syndrome 334

6.3.2 Rheumatoid Arthritis 335

6.3.3 Dermatological Disorders 335

6.3.4 Other Conditions 336

7 Toxicity 336

7.1 General Effect of Immunosuppression 336

7.2 Specific Toxicity 337

7.3 Nephrotoxicity 337

7.3.1 Acute Toxicity 338

7.3.2 Chronic Toxicity 338

7.3.3 Thrombotic Microangiopathy 339

7.3.4 Management 340

7.4 Hypertension 341

7.5 Dyslipidaemia 342

7.6 Diabetes Mellitus 342

7.7 Neurotoxicity 342

7.8 Other Side Effects 343

8 Pharmacokinetics and Drug Interactions 343

9 Therapeutic Drug Monitoring 347

10 Conclusion 348

References 348

Abstract T cells play a key role in orchestrating the immune response to an allograft. The discovery of a potent and immunologically specific inhibitor of T cell activation, ci-closporin, dramatically improved the results of renal transplantation and transformed other types of organ transplantation from experimental to standard therapy. The discovery of a second drug, tacrolimus, that was structurally unrelated to ciclosporin but which had an identical mechanism of action, facilitated research which clarified the mechanisms underlying T cell activation. Although these drugs are powerful immunosuppressants, their clinical use is limited by their nephrotoxicity. In transplantation, this has led to their use in lower doses in combination with other immunosuppressive drugs. However long-term nephrotoxicity remains a significant problem, and this has curtailed the use of calcineurin-inhibitors for indications outside the field of transplantation. Ciclosporin and tacrolimus are metabolised by cytochrome P450 3A and are substrates for the P-gly-coprotein transporter system. This results in complex pharmacokinetics with large variations in bioavailability and metabolism between individuals as well as a great number of clinically significant drug interactions. Therapeutic drug monitoring has been used to address these issues. For the foreseeable future, these powerful immunosuppressive agents are likely to continue to play a role in organ transplantation. However, newer im-munosuppressants that are not nephrotoxic may begin to replace calcineurin-inhibitors for long-term maintenance therapy after transplantation.

Keywords Ciclosporin ■ Cyclosporine ■ Tacrolimus ■ Calcineurin-inhibitor ■ Immunosuppression ■ Transplantation ■ Nephrotoxicity ■ Autoimmune disease

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