Cyclosporin A

Absorption

The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose.
The Cmax of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily.
A note on erratic absorption
During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability.

Toxicity

The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg.
Overdose information
In cases of overdose with oral cyclosporine, forced emesis and gastric lavage are recommended 2 hours after ingestion. There are little data available in the literature regarding overdoses with cyclosporine, but hepatotoxicity and nephrotoxicity may occur. One case report of an cyclosporine overdose due to medical error was made involving a 26 year old female and noted the occurrence of nausea, flushing, tremor, vertigo and vomiting, which resolved within about 1 day. Anorexia and a feeling of increased body girth were also experienced by this patient and resolved within about 2 weeks. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal, hemoperfusion are not effective techniques to remove cyclosporine from the body.

Description

Cyclosporine A is a powerful immunosuppressive drug intended for preventing rejection of kidney, heart, and lung transplants. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground.
Cyclosporine A is the first drug to affect a specific line of protecting cells of the body. Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously. Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possibility of treating autoimmune system diseases.

Chemical properties

White or almost white powder

Chemical properties

White crystalline solid or powder.

Originator

Sandimmune,Sandoz,US,1983

The Uses of Cyclosporin A

Cyclosporin A is a hydrophobic cyclic peptide isolated from several fungal species including Cylindrocarpon, Fusarium, Trichoderma and Tolypocladium. Cyclosporin A inhibits T-cell activation and has been marketed since 1983 as an immunosuppressant in post-allogeneic organ transplant. Cyclosporin A acts by binding to the protein, cyclophilin (immunophilin), in T-lymphocytes causing inhibition of calcineurin (protein phosphatase 2B). Cyclosporin A reduces transcription of interleukin 2, and inhibits lymphokine production, interleukin release and NO synthesis induced by interleukin 1α, lipopolysaccharides and TNFα.

The Uses of Cyclosporin A

An immunosuppressant that has revolutionized organ transplantation through its use in the prevention of graft rejection. A group of nonpolar cyclic oligopeptides with immunosupppressant activity.

The Uses of Cyclosporin A

prothrombogenic agent

Indications

Cyclosporine is approved for a variety of conditions. Firstly, it is approved for the prophylaxis of organ rejection in allogeneic kidney, liver, and heart transplants. It is also used to prevent bone marrow transplant rejection. For the above indications, cyclosporine can be used in conjunction with azathioprine and corticosteroids. Finally, cyclosporine can be used in patients who have chronic transplant rejection and have received previous immunosuppressive therapy and to prevent or treat graft-versus-host disease (GVHD).
Secondly, cyclosporine is used for the treatment of patients with severe active rheumatoid arthritis (RA) when they no longer respond to methotrexate alone. It can be used for the treatment of adult non-immunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated. The ophthalmic solution of cyclosporine is indicated to increase tear production in patients suffering from keratoconjunctivitis sicca. In addition, cyclosporine is approved for the treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases which may include minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis.
A cyclosporine ophthalmic emulsion is indicated in the treatment of vernal keratoconjunctivitis in adults and children.
Off-label, cyclosporine is commonly used for the treatment of various autoimmune and inflammatory conditions such as atopic dermatitis, blistering disorders, ulcerative colitis, juvenile rheumatoid arthritis, uveitis, connective tissue diseases, as well as idiopathic thrombocytopenic purpura.

What are the applications of Application

Cyclosporin A is a fungal metabolite calcineurin and mitochondrial permeability transition pore opening inhibitor.

Background

Cyclosporine is a calcineurin inhibitor known for its immunomodulatory properties that prevent organ transplant rejection and treat various inflammatory and autoimmune conditions. It is isolated from the fungus Beauveria nivea. Initially manufactured by Sandoz and approved for use by the FDA in 1983, cyclosporine is now available in various products by Novartis (previously known as Sandoz).

Definition

ChEBI: A cyclic nonribosomal peptide of eleven amino acids; an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient's immune system, and therefore the risk of organ rejection. Also causes reversible inhibiti n of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle.

Indications

Manufacturing Process

10 liters of a nutrient solution (of which each liter contains 30 g of sucrose, 10 g of corn steep, 3 g of NaNO3, 1 g of K2HPO4, 0.5 g of MgSO4·7H2O, 0.5 g of KCl and 0.01 g of FeSO4·7H2O) are inoculated with 100 cc of a conidia and mycelium suspension of the strain NRRL 5760, and incubation is effected in 700 cc penicillin flasks at 27°C for 11 days.
The mycelium, which has been separated from the culture liquid, is extracted in a Turrax apparatus by crushing and stirring with 3.5 liters of 90% methanol, and the crushed mycelium, which is separated from the solvent by filtering with suction, is again treated twice in the same manner with 90% methanol. The combined filtrates are concentrated by evaporation in a vacuum at a bath temperature of 40°C to such an extent that the vapor mainly consists of water alone. The resulting mixture is extracted six times with the same volume of ethylene chloride by shaking, whereupon the combined ethylene chloride solutions are purified by extraction with water and are concentrated by evaporation in a vacuum at a bath temperature of 40°C. The resulting residue is chromatographed on 250 g of silica gel (silica gel 60 Merck, grain size 0.063-0.200 mm), using chloroform containing 2% of methanol as eluant, and is collected in 200 cc fractions. The fractions which are antibiotically active against Aspergillus niger in the plate diffusion test are combined, evaporated to dryness as described above, and after dissolving in methanol are chromatographed on 110 g of Sephadex LH20 with the same solvent, whereupon those 20 cc fractions showing an antibiotic effect against Aspergillus niger in the test indicated above, are combined. A test in the thin layer chromatogram, e.g., with silica gel on Polygram foils and hexane/acetone (1:1) as eluant, indicates that the residue of the methanol solution evaporated as described above mainly consists of the two new antibiotics S 7481/F-1 and S 7481/F-2. These are separated and simultaneously purified by a further chromatography of the mixture thereof, using a 1,000-fold amount of silica gel on the above indicated quality and chloroform contains 2% of methanol. A testing of the eluate fractions having a volume in milliliters which is half as large as the weight of the silica gel in grams, in the thin layer chromatogram, indicates that the antibiotic S 7481/F- 1 appears first in the eluate, followed by a mixture of the two antibiotics and finally by homogeneous S748l/F-2.
Further amounts of the two antibiotics may be obtained from the mixture by repeating chromatography under the same conditions.

brand name

Gengraf (Abbott); Neoral (Novartis); Restasis (Allergan); Sandimmune (Novartis) [Names previously used: Cyclosporin A; Cyclosporin.].

Therapeutic Function

Immunosuppressive

General Description

White prismatic needles (from acetone) or white powder.

Air & Water Reactions

Slightly water soluble .

Reactivity Profile

Cyclosporin A is an amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Health Hazard

SYMPTOMS: Symptoms of exposure to Cyclosporin A include hepatotoxicity, nephrotoxicity, hyperkalemia, hyperuricemia, convulsions, renal dysfunction, tremor, hirsutism, hypertension, gum hyperplasia, cramps, acne, headache, diarrhea, nausea, vomiting, abdominal discomfort, paresthesia, flushing, leukopenia, lymphoma, sinusitis and gynecomastia. In 2% or less of persons exposed, it has caused allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia and tinnitus. Rare reactions include anxiety, chest pain, constipation, depression, hair breaking hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper gastrointestinal bleeding, visual disturbance, weakness and weight loss. It has caused kidney and liver damage. An increased susceptibility to infection may occur. Other symptoms include gastrointestinal disturbance, rashes and angioedema.

Fire Hazard

Flash point data for Cyclosporin A are not available; however, Cyclosporin A is probably combustible.

Biochem/physiol Actions

Cyclosporin A is a non-polar cyclic oligopeptide produced by the fungus Tolypocladium inflatum. It is a potent immunosuppressive agent, affecting primarily T-lymphocytes. It has been shown to inhibit the functioning of several nuclear proteins involved in T-cell activation at the level of mRNA transcription. It forms a complex with its intracellular receptor cyclophilin, which can then bind to calcineurin, a Ca2+- and calmodulin-dependent protein phosphatase, inhibiting its enzymatic activity. CsA was found to suppress the replication of hepatitis C virus genome in cultured hepatocytes. At concentrations >10 nM, CsA protected isolated hepatocytes against the action of phalloidin. CsA can inhibit IL2 production resulting from T cell activation via Calcineurin inhibition.An extensive list of references has been reported, including a comprehensive review of analytical properties.

Pharmacokinetics

Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease.
Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity.

Pharmacology

Cyclosporine has no direct effect on keratinocytes and is not a mitotic inhibitor. Cyclosporine inhibits cytokine release, which results in a decreased recruitment of APCs into the epidermis and decreases immunoreactivity of lesions. Potential long-term side effects preclude cyclosporine’s use in all but very severe and recalcitrant psoriasis. Cyclosporine can be combined with lowdose methotrexate.

Clinical Use

Immunosuppressant:
Prophylaxis of solid organ transplant rejection

Nephrotic syndrome

Atopic dermatitis

Psoriasis

Rheumatoid arthritis

Ulcerative colitis

Side Effects

Cyclosporine’s main side effects, even at low doses, are hypertension and nephrotoxicity. Age, baseline blood pressure, and baseline creatinine levels are predictors of higher risks of side effects. Glomerular filtration rate (GFR) is a more sensitive test than creatinine for evaluating renal function, and a baseline is recommended in any high-risk patient. Longterm treatment with CSA may induce interstitial fibrosis and glomerular sclerosis, with more pronounced changes directly associated with duration of therapy. It should be administered only by dermatologists experienced in its use.

Safety Profile

Confirmed carcinogen producing Hodghn's dlsease. Experimental reproductive effects. Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion. Human systemic effects by ingestion: increased body temperature, cyanosis. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Cyclosporine A, [R-[R* ,R* -(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-Lleucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14–17], and which is also proposed to obtain synthetically.

Potential Exposure

Cyclosporin A is a fungal metabolite; an amide immunosuppressant drug used in various surgeries.

Drug interactions

Potentially hazardous interactions with other drugs
Increased risk of hyperkalaemia with ACE inhibitors, angiotensin-II antagonists, potassiumsparing diuretics, potassium salts.
Increased risk of nephrotoxicity with aminoglycosides, amphotericin, co-trimoxazole, disopyramide, foscarnet, melphalan, NSAIDs, polymyxins, quinolones, sulphonamides, thiazide diuretics, trimethoprim and vancomycin.
Increased ciclosporin levels with acetazolamide, aciclovir, amiodarone, atazanavir, boceprevir, carvedilol, chloramphenicol, chloroquine, cimetidine, danazol, diltiazem, doxycycline, famotidine, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, glibenclamide, glipizide, grapefruit juice, hydroxychloroquine, imatinib, indinavir, itraconazole, ketoconazole, lercanidipine (concentration of both drugs increased - avoid), macrolides, micafungin, miconazole, high-dose methylprednisolone, metoclopramide, metronidazole, muromonabCD3, nicardipine, posaconazole, progestogens, propafenone, ritonavir, saquinavir and telaprevir (concentration of both drugs increased), tacrolimus, verapamil and voriconazole.
Decreased ciclosporin levels with barbiturates, bupropion, carbamazepine, efavirenz, fosphenytoin, griseofulvin, lanreotide, modafinil, octreotide, pasireotide, phenytoin, primidone, quinine, red wine, rifampicin, St John’s wort, sulfadiazine, IV sulfadimidine, sulfasalazine, sulfinpyrazone,terbinafine, ticlopidine and IV trimethoprim and possibly by oxcarbazepine.
Aliskiren: concentration of aliskiren increased - avoid.
Ambrisentan: concentration of ambrisentan increased.
Antibacterials: increased risk of myopathy with daptomycin - try to avoid concomitant use.
Anticoagulants: concentration of dabigatran and edoxaban increased - avoid with dabigatran and reduce dose of edoxaban.
Antidiabetics: may increase repaglinide concentration, risk of hypoglycaemia.
Antimuscarinics: avoid with darifenacin.
Antivirals: avoid with simeprevir, increased simeprevir concentration; when starting coadministration with dasubavir and ombitasvir/ paritaprevir/ritonavir, give one fifth of the total daily dose of ciclosporin once daily. Monitor ciclosporin levels and adjust dose and/or dosing frequency as needed.
Basiliximab: may alter ciclosporin levels.
Bosentan: co-administration of ciclosporin and bosentan is contraindicated. When ciclosporin and bosentan are co-administered, initial trough concentrations of bosentan are 30 times higher than normal. At steady state, trough levels are 3-4 times higher than normal. Blood concentrations of ciclosporin decreased by 50%.
Calcium-channel blockers: increased nifedipine concentration and toxicity; amlodipine may increase ciclosporin concentration by up to 40%.
Cardiac glycosides: increased digoxin concentration and toxicity.
Caspofungin: caspofungin concentration increased - monitor LFTs.
Colchicine: risk of myopathy or rhabdomyolysis; also increased blood-ciclosporin concentrations and nephrotoxicity - avoid.
Cytotoxics: increased risk of neurotoxicity with doxorubicin; concentration of epirubicin, everolimus and idarubicin increased; reduced excretion of mitoxantrone; increased toxicity with methotrexate; seizures have been reported in bone marrow transplant patients taking busulfan and cyclophosphamide; use crizotinib with caution; concentration of etoposide possibly increased (increased risk of toxicity); possible interaction with docetaxol.
Eltrombopag: exposure reduced by ciclosporin.
Fidaxomicin: avoid concomitant use.
Lenalidomide: concentration of lenalidomide increased.
Lipid-lowering agents: absorption reduced by colesevelam, increased risk of myopathy with statins (avoid with simvastatin, max dose of atorvastatin should be 10 mg1 ); avoid with rosuvastatin; increased risk of nephrotoxicity with fenofibrate; bezafibrate may increase creatinine and reduce ciclosporin levels; concentration of both drugs may be increased with ezetimibe.
Mycophenolate mofetil: some studies show that ciclosporin decreases plasma MPA AUC levels - no dose change required.
NSAIDs: diclofenac concentration increased - reduce diclofenac dose.
Omeprazole: may alter ciclosporin concentration.
Orlistat: absorption of ciclosporin possibly reduced.
Prednisolone: increased prednisolone concentration.
Rifaximin: concentration of rifaximin increased.
Sirolimus: increased absorption of sirolimus - give sirolimus 4 hours after ciclosporin; sirolimus concentration increased; long term concomitant administration may be associated with deterioration in renal function.
Tacrolimus: increased ciclosporin concentration and toxicity - avoid.
Ursodeoxycholic acid: unpredictably increased absorption and raised ciclosporin levels in some patients.

Carcinogenicity

Cyclosporin A is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.

Metabolism

Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies.
The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.

Metabolism

Ciclosporin is widely distributed throughout the body. Distribution in the blood is concentration-dependent, with between 41-58% in erythrocytes and 10-20% in leucocytes; the remainder is found in plasma, about 90% protein-bound, mostly to lipoprotein.
Clearance from the blood is biphasic. Ciclosporin is extensively metabolised in the liver and mainly excreted in faeces via the bile. About 6% of a dose is reported to be excreted in the urine, less than 0.1% unchanged.

storage

-20°C (desiccate)

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Incompatibilities

Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents such as hydrideds and active metals. Amides are very weak bases (weaker than water). Imides are less basic yet and in fact react with strong bases to form salts. That is, they can react as acids. Mixing amides with dehydrating agents such as such as phosphorus pent- oxide or thionyl chloride generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Waste Disposal

t is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consider- ation applicable DEA, EPA, and FDA regulations. If possi- ble return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged, and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

References

1) Liu et al. (1993), FK506 and cyclosporin: molecular probes for studying intracellular signal transduction; Trends Pharmacol. Sci., 18 334