ciclosporin
cyclosporine (USAN), cyclosporin A, ciclosporin A, CsA, OL 27-400
Ciclosporin is a cyclic peptide of eleven amino acids produced by the fungus Tolypocladium inflatum, and it is arguably the single most consequential peptide medicine ever discovered. It made solid organ transplantation routine. It is an immunosuppressant, not an oncology drug, and is filed in this collection because it is the archetypal therapeutic cyclic peptide. It works by an unusual indirect mechanism, forming a complex with the intracellular protein cyclophilin A which then inhibits the phosphatase calcineurin and shuts down T-cell activation.
Mechanism
Ciclosporin is a cyclic undecapeptide, and its behaviour is dictated by an extraordinary degree of chemical modification: seven of the eleven amide nitrogens are N-methylated, one residue is a D-amino acid, and position 1 carries the unusual residue MeBmt, (4R)-4-[(E)-2-butenyl]-4-methyl-L-threonine. The N-methylation removes hydrogen bond donors and lets the molecule adopt a conformation with an internal hydrogen bond network, giving it enough lipophilicity to cross cell membranes despite a molecular weight above 1,200. This is the textbook example of a peptide escaping the rule of five.
Inside the cell it binds cyclophilin A, an abundant peptidyl-prolyl cis-trans isomerase. Neither ciclosporin nor cyclophilin alone inhibits anything relevant; it is the composite ciclosporin-cyclophilin surface that docks into calcineurin, the calcium/calmodulin-dependent serine-threonine phosphatase, and blocks access of substrates to its active site. The critical substrate is NFAT (nuclear factor of activated T cells). On T-cell receptor engagement, rising intracellular calcium activates calcineurin, which dephosphorylates NFAT and exposes its nuclear localisation signal; NFAT enters the nucleus, partners with AP-1, and drives transcription of interleukin-2, interleukin-4, interferon gamma, CD40 ligand and GM-CSF. With calcineurin inhibited, NFAT stays phosphorylated and cytoplasmic, the interleukin-2 autocrine loop never starts, and T cells arrest in G0/G1. Both helper and cytotoxic T-cell clonal expansion is suppressed; B-cell effects are largely secondary to lost T-cell help.
Two other actions are worth knowing. Ciclosporin binds cyclophilin D in mitochondria and inhibits opening of the mitochondrial permeability transition pore, which is the basis of an entire research literature in ischaemia-reperfusion injury, muscular dystrophy and neuroprotection, and is unrelated to immunosuppression. And it inhibits P-glycoprotein, which underlies both some of its drug interactions and its historical use as a chemosensitiser in multidrug-resistance research.
What the research shows
The foundational evidence came from two independent multicentre randomised trials published in 1983. The Canadian Multicentre Transplant Study Group randomised 209 recipients of cadaveric renal transplants to ciclosporin and prednisone or to azathioprine and prednisone, reporting one-year graft survival of 80% versus 64%. The European Multicentre Trial randomised 232 recipients across eight centres with similar results. The three-year analysis from the Canadian group, reporting on 291 recipients (142 ciclosporin, 149 control), found graft survival of 69% versus 58% (p = 0.05) and patient survival of 90% versus 82% (p = 0.04), while also documenting that serum creatinine was persistently poorer in the ciclosporin arm, the first clear signal of the nephrotoxicity that would define the drug's long-term limits. These are the trials that turned transplantation from a specialist gamble into a routine operation; before ciclosporin, one-year cadaveric renal graft survival hovered around 50%.
Beyond transplantation, randomised evidence accumulated across autoimmune disease. A 16-week multidose double-blind trial in 85 patients with severe plaque psoriasis found a clean dose-response: after eight weeks of fixed dosing, 36%, 65% and 80% of patients receiving 3, 5 and 7.5 mg/kg/day respectively were rated clear or almost clear, against none on vehicle, with higher doses producing greater falls in glomerular filtration rate and rises in blood pressure. In severe ulcerative colitis refractory to intravenous corticosteroids, an early uncontrolled study of 32 patients reported an 80% response rate, and a subsequent small randomised double-blind trial in 20 patients found that 9 of 11 (82%) responded to intravenous ciclosporin against 0 of 9 on placebo, a striking effect size from a very small trial, which nonetheless established ciclosporin as a rescue option before biologics existed. Two multicentre randomised studies of a 0.05% ophthalmic emulsion in 877 patients with moderate to severe dry eye disease found significant improvement in corneal staining and Schirmer tear production. Ciclosporin has also been studied, less successfully, in type 1 diabetes (where it does delay beta cell loss while it is being taken but the effect disappears on withdrawal and the nephrotoxicity was unacceptable) and in amyotrophic lateral sclerosis and other neurological conditions where the mitochondrial permeability transition pore rationale has not translated into clinical benefit.
Evidence assessment
High-quality evidence
Four decades of regulator-approved labelling across many jurisdictions and indications, supported by two independent randomised controlled trials in cadaveric renal transplantation published in 1983 with a three-year confirmatory analysis, plus randomised trials in psoriasis, ulcerative colitis and dry eye disease. All seven citations were individually verified against PubMed; two substantive misstatements of trial results in the draft (the psoriasis dose-response and the design of the 1994 ulcerative colitis trial) were corrected. Among the best-established medicines in the pharmacopoeia.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A randomized clinical trial of cyclosporine in cadaveric renal transplantation Preclinical only
One-year graft survival 80% with ciclosporin versus 64% with azathioprine. One of the two trials that established calcineurin inhibition as the foundation of transplant immunosuppression.
Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial Preclinical only
Independent replication in a separate healthcare system of the graft survival advantage of ciclosporin over conventional azathioprine-based immunosuppression.
A randomized clinical trial of cyclosporine in cadaveric renal transplantation. Analysis at three years Preclinical only
Graft survival 69% versus 58% (p = 0.05) and patient survival 90% versus 82% (p = 0.04) at three years. Renal function was persistently poorer in the ciclosporin arm though stable after month six, the first clear documentation of the chronic nephrotoxicity that became the drug's defining limitation.
Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial Preclinical only
After eight weeks of fixed dosing, 36%, 65% and 80% of patients on 3, 5 and 7.5 mg/kg/day respectively were rated clear or almost clear, versus none on vehicle (p < 0.0001 for each dose). Higher doses produced greater falls in glomerular filtration rate and rises in blood pressure; 5 mg/kg/day was concluded to be the appropriate starting dose.
Preliminary report: cyclosporin in treatment of severe active ulcerative colitis Preclinical only
80% of 32 patients responded to ciclosporin. The uncontrolled design is a serious limitation, and this result generated the hypothesis that the 1994 randomised trial went on to test.
Cyclosporine in severe ulcerative colitis refractory to steroid therapy Preclinical only
9 of 11 patients (82%) treated with intravenous ciclosporin responded within a mean of seven days, versus 0 of 9 on placebo (p < 0.001). A very large effect from a very small trial; it established ciclosporin as a rescue option to avoid urgent colectomy before biologic therapy existed.
Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease Preclinical only
Significant improvement in corneal staining and Schirmer tear production with 0.05% and 0.1% ciclosporin ophthalmic emulsion versus vehicle; the 0.05% concentration also improved symptoms including blurred vision and reduced artificial tear use.
Safety
Nephrotoxicity is the dominant long-term problem and comes in two forms: an acute, dose-dependent, reversible haemodynamic effect from afferent arteriolar vasoconstriction, and a chronic, largely irreversible interstitial fibrosis with tubular atrophy and arteriolar hyalinosis that limits how long the drug can be used at effective doses. Hypertension is very common and often requires treatment. Metabolic effects include hyperlipidaemia, hyperkalaemia, hypomagnesaemia, hyperuricaemia with gout, and impaired glucose tolerance. Neurological effects range from the very common fine tremor and headache to rare posterior reversible encephalopathy syndrome and seizures. Gingival hyperplasia and hypertrichosis are characteristic and cosmetically distressing. Immunosuppression brings increased susceptibility to bacterial, viral, fungal and opportunistic infection, and an increased long-term risk of malignancy, particularly cutaneous squamous cell carcinoma and post-transplant lymphoproliferative disorder. The interaction burden is exceptional: as a CYP3A4 and P-glycoprotein substrate, exposure is raised by azole antifungals, macrolide antibiotics, protease inhibitors, verapamil, diltiazem and grapefruit juice, and lowered by rifampicin, carbamazepine, phenytoin and St John's wort; ciclosporin in turn raises statin exposure with a risk of rhabdomyolysis. The therapeutic index is narrow, whole-blood concentration monitoring is routine, and oral formulations are not interchangeable.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Long-established MHRA licensing for prophylaxis and treatment of transplant rejection (kidney, liver, heart, heart-lung, lung, pancreas), bone marrow transplantation and graft-versus-host disease, and for severe psoriasis, severe atopic dermatitis, severe active rheumatoid arthritis, nephrotic syndrome and non-infectious uveitis. Topical ophthalmic formulations are licensed for severe keratitis in dry eye disease. Prescribing by product is recommended because oral formulations differ in bioavailability; therapeutic drug monitoring of whole-blood concentrations is standard. |
| United States | FDA approved 1983 for prophylaxis of organ rejection in kidney, liver and heart allogeneic transplants. A modified microemulsion formulation with more consistent absorption was approved in 1995 and is not bioequivalent to the original oil-based formulation. Further approvals cover severe active rheumatoid arthritis and severe recalcitrant plaque psoriasis (both 1997), and a topical ophthalmic emulsion for keratoconjunctivitis sicca (2002). Multiple generic products exist. Prescribing requires attention to formulation, since products are not interchangeable. |
| WADA (sport) | Not on the WADA Prohibited List. Ciclosporin is an immunosuppressant with no anabolic, hormonal, stimulant or diuretic action, and it is not a masking agent. |
Questions
Through an unusual bit of chemistry. Seven of ciclosporin's eleven amide nitrogens are methylated, which removes hydrogen bond donors and lets the molecule fold with an internal hydrogen bond network that hides its polar groups. The result is a large peptide that behaves like a lipophilic small molecule. It is the standard teaching example of how nature breaks the rule of five.
Neither ciclosporin nor cyclophilin A inhibits calcineurin on its own. It is the composite surface formed when they bind each other that docks onto calcineurin and blocks substrate access. This 'molecular glue' mechanism was surprising when it was worked out and has since become a deliberate drug design strategy.
Because oral formulations are genuinely not interchangeable. The original oil-based preparation has erratic, bile-dependent absorption of around 30%, whereas the microemulsion formulation absorbs more completely and more consistently. Switching between them without dose adjustment and blood level monitoring risks either rejection or toxicity.
Chronic nephrotoxicity. Beyond the reversible haemodynamic effect on renal blood flow, prolonged exposure causes interstitial fibrosis, tubular atrophy and arteriolar hyalinosis that do not reverse. The three-year analysis of the Canadian transplant trial already showed persistently poorer renal function in the ciclosporin arm. This is why long-term transplant protocols aim to minimise calcineurin inhibitor exposure, and why ciclosporin courses in psoriasis and atopic dermatitis are usually time-limited.
From a fungus, Tolypocladium inflatum, isolated from a soil sample and screened for antifungal activity at a Basel laboratory in the early 1970s. Its antifungal activity was mediocre; the immunosuppressive effect was found later and turned out to be one of the most important pharmacological discoveries of the twentieth century.