1970, isolated as narrow antifungal from Tolypocladium inflatum Gams o 1976, found to be a potent immunosuppressive o 1983, FDA approval

for transplant rejection. o 1997, FDA approval for Rx of psoriasis o Approved for atopic dermatitis in other countries.
o

 Cyclic polypeptide Consist of 11 amino acids Produced as a metabolite by Beauveria nivea.

Pharmacokinetics
Absorption and bioavailability
Before meal higher absorption Widely distributed Ideal body weight should be used to calculate dose Bioavailabl e (%) Protein binding (%)

Elimination

First-order kinetics

Peak levels (hr)

Half-life (hr)

Metabolism

Excretion

2-4

30

90

5-18

CYP3A4 and CYP3A5 in liver Efflux pglycoprotein pump (PGP), in GI tract and liver

Primarily hepatobilia ry Renal 6%

o Sandimmune (cyclosporine, USP) o Gengraf (cyclosporine, USP Modified) o Neoral (cyclosporine, USP Microemulsion)

o o

Twice the bioavailability Less intraindividual and interindividual variability Reduced time (more than 30 percent) to maximal concentration (Tmax)

Absorption and drug levels are less susceptible to effects of food (particularly fatty foods),
Not dependent upon bile salts for absorption.

o o o

1. Action on the calcineurin / NFAT pathway 2. Action on JNK and p38 signaling pathways 3. Action by Induction of TGF-b

Action on calcineurin / NFAT pathway

JNK and p38 act in stress responses, (inflammation and apoptosis), o Activated when T cell responses are triggered through both TCR and CD28 co-stimulatory receptor o Are sensitive to CsA (Su et al., 1994;Matsuda et al., 1980) . o JNK and p38 with ERK leads to activation of transcription factors including AP-1 (Karin, 1995)
o

o
o o o

CsA induces synthesis of TGF-b in vitro and in vivo (Li et al., 1991; Khanna et al., 1994; Wolf et al.,1995; Shihab et al., 1996) TGF-b is known to stimulate cells to increase their extracellular matrix ECM composition Decreases production of ECM-degrading proteases, Thereby inducing a profibrogenic state (Massague,1990) . TGF-b produced by CsA administration directly promotes cancer progression (Hojo et al., 1999) .

US FDA approved
Psoriasis Severe Psoriasis Recalcitrant, treatment resistant Psoriasis Disabling Psoriasis

Approved in other countries

Psoriasis Atopic dermatitis

Disease

CsA dose

Duration of Rx 12-16 wks, 12 mos maximum

Response Time to relapse after discontinued Excellent

Other drugs

Comm ents

Psoriasis

Average 111 days; however, 30% had no relapse 6 mos after CsA discontinued

A. Intermittent short-term therapy B. Rescue therapy C. Long term therapy D. Combination therapy E. Rotational therapy

2.5-5 mg/kg/day for 12-16 wks, course repeated when relapse occurs

5 mg/kg/day for 12-16 wks for flaring of disease <5 mg/kg/day for up to 1 y; reducing dose to lowest effective Corticosteroids, anthralin, or vitamin D3 analogues for an improved response. MTX, fumaric acid esters, and mycophenolate mofetil in severe cases Can minimize CsA toxicity

Disease

CsA dose

Duratio n of treatme nt

Response Time to relapse Other after discontinued drugs

Comments

Psoriatic arthritis

3-4 6-12 mos Very good mg/kg/da y, max 5 mg/kg/da y

MTX 15 mg/wk, occasio nally

50% reduction in joint complaints required 24 wks of CsA monotherapy, CsA-MTX combination therapy given to patients with partial MTX response Used for short treatment of severe, AD that cannot be controlled with topical therapy. Approved for this in Europe and UK

Atopic dermatitis

2.5-3 12-16 Excellent mg/kg/da wks, 12 y, max 5 mos max mg/kg/da y 5 >6 mos mg/kg/da y Excellent

2 wks (50%), 6 wks (80%)

Pyoderma gangrenosu m

Methylprednisolo ne (0.5-1 mg/kg/day, or pulse treatment 1 g/day for 1-5 days) usually given concurrently

Disease

CsA dose

Duration of Response treatment

Time to relapse after discontinued

Other Comments drugs

Dyshidrotic 2.5-3 mg/kg/day eczema

6 wks, up to 16 wks

Equivalent

77% of patients continued to have a 54% improvement at 1 y Prednisone, occasionally

CsA equivalent to BDP cream

Behet disease

5 mg/kg/day >6 mos

Very good

Used for refractory eye disease, topical steroidresistant mucocutaneous disease, and arthritis. Poor prevention of neurologic involvement

Chronic urticaria

4 mg/kg/day 12-16 wks

Very good

33% at 3-6 mos, relapse less severe Cetirizine 10 mg/day, occasionally concurrently

Used as a steroid sparing agent or in cases refractory to corticosteroids

Disease

CsA dose

Duration of treatment

Response

Time to relapse after discontinued

Other drugs

Comments

Pityriasis rubra pilaris

3-5 >8 mos mg/kg/day, maintenance dose 2 mg/kg/day

1-1.8 mg/kg/day, >200 mg/day

Mixed

Used in erythrodermic classic adult and erythrodermic juvenile PRP

Dermato myositis

Very good

Prednisone 40 mg/day

Used in cases not responsive to prednisone combined with MTX or azathioprine. Effective for lung and esophageal involvement Prednisone, usually given concurrently Used as a steroid sparing agent

Pemphigus 1-3 vulgaris mg/kg/day

8 mos 11.8 mos

Good, but better treatment options available

43% free of relapse after combination therapy with cyclosporine and prednisone 5 y after discontinuation of therapy

Disease

CsA dose

Duration of treatment
1-24 mos

Response

Time to relapse Other drugs after discontinued

Comments

Epidermolysis 4-5 bullosa mg/kg/d acquisita ay

Good, but better treatment options available

Prednisone, Used as usually given steroid concurrently sparing agent

Photodermatoses A. Chronic actinic dermatitis 4-4.5 mg/kg/day Good

B. 3-4 Polymorphic mg/kg/day light eruption C. Solar urticaria

May be given 1 wk before sun exposure, and discontinued upon return

Good

4.5 Short courses during mg/kg/day summer months

Flares once cyclosporine discontinued

Disease

CsA dose

Duration Response Time to relapse of after discontinued treatment

3-5 mos Good Symptom free, stable disease at 12 mos postcyclosporine

Other drugs

Comments

Lichen 3-5 planopilaris mg/kg /day

CsA may be effective in the initial phases before severe follicular damage occurs

Prurigo nodularis

3.5-4 mg/kg /day 3-4.5 mg/kg /day

6-9 mos

Good

Lichen planus

2-3 mos

Good

Prednisone, occasionally topical steroids

Used for disseminated , erosive LP, and LP resistant to systemic corticosteroids and retinoids. Topical CsA may be effective in treatment of oral LP

Disease

CsA dose Duration of treatment 5 mg/kg/da y 2-12 mos

Response Time to relapse after discontinued

Other drugs

Comments

Severe alopecia areata

Mixed 33%-86% with >70% hair regrowth, 76% with maintained hair regrowth at 12 mos followup Good

Methylpredn isolone (pulse and daily dosing), prednisone

Eight case reports of patients who developed alopecia areata while on CsA for solid organ transplant, and atopic dermatitis

Hailey-Hailey 1.2-3.4 Ds. mg/kg/da y Eosinophilic pustular folliculitis Hidradenitis suppurativa 100-150 mg/day

6-8 mos

Acitretin 10 mg/day, occasionally

2-12 wks

Good

4-4.5 mg/kg/da y

Good

Prednisolone, broad spectrum antibiotics

Scleroderma

May potentially worsen hypertension or renal disease associated with systemic sclerosis

o
o o o

o
o o o

o
o o o

Pemphigoid Linear IgA bullous dermatosis Lupus erythematosus Granuloma annulare Sarcoidosis Kimuras ds. Morphea Papular erythroderma of ofuji Purpura pigmentosa chronica Reiters syndrome Scleromyxedema Sezarys syndrome Mycosis fungoides

Department of Dermatology, Health Waikato, New Zealand. o Abstract o A patient developed toxic epidermal necrolysis while on carbamazepine, 80% of her skin surface being involved. She also developed a pancytopenia with a neutropenia of 0.77 x 10(9)/l (normal range 2-7.5 x 10(9)/l), but was treated with cyclosporin and granulocyte colony stimulating factor and made a full recovery. o Int J Dermatol. 1989 Sep;28(7):441-4.
o

Drug-induced toxic epidermal necrolysis treated with cyclosporin. Renfro L, Grant-Kels JM, Daman LA. Division of Dermatology, University of Connecticut Health Center, Farmington. Abstract A 35-year-old woman developed toxic epidermal necrolysis secondary to phenytoin. Because the life-threatening eruption was resistant to prednisone and high-dose methylprednisolone therapy, cyclosporine therapy was initiated. Within 24-48 hours, the eruption stabilized and the patient improved.

ABSOLUTE

Uncontrolled

o RELATIVE

hypertension, Significant renal impairment, Serious infections, Previous history of malignancy, excluding BCC High cumulative dose of previous psoralen and ultraviolet A light phototherapy Cutaneous T-cell lymphoma

o o o

Drugs that inhibit or stimulate cytochrome P450 Nephrotoxic drugs should be avoided A full drug history should be taken at every visit

Calcium channel blockers Diltiazem, nicardipine, verapamil, and mibefradil Antifungals Ketoconazole > itraconazole > Fluconazole, and voriconazole Antibiotics Erythromycin, clarithromycin, and josamycin, Doxycycline, Gentamicin and tobramycin, Ticarcillin, Ciprofloxacin Oral contraceptives

o o o o o o

Amiodarone Cimetidine Protease inhibitors Warfarin Grapefruit juice SSRIs (sertraline)

By other mechanism o Methylprednisolone o Allopurinol o Thiazide diuretics o Furosemide

Anticonvulsants (carbamazepine, phenobarbitone, phenytoin, and valproate) o Rifampicin o Rifabutin o Isoniazid o Griseofulvin
o

o o o o o o

Probucol Ticlopidine Nafcillin Octreotide Orlistat Bexarotene

Drug Type

Comments

Nephrotoxic agents

NSAIDs Vancomycin Ganciclovir Aminoglycosides

Monitor renal function NSAIDs may have increased nephrotoxicity with hepatic impairment

Potassium-sparing diuretics Antacids

Hyperkalemia has been reported Magnesium and aluminum antacids may inhibit absorption of CNIs If necessary, should be taken 2 hours after CNI dose

HMG-CoA reductase inhibitors

(statins)

Increased risk of rhabdomyolysis, bone marrow suppression

o o o o o o

Are leading cause of its limited use in dermatology. Depend on dose and duration of therapy Reversible on discontinuation, Structural renal abnormalities may be persistent. Mitochondrial dysfunction (ion channel regulation) Inhibition of immunophilins may play a role

Event Renal dysfunction o Functional

Vascular dysfunction Tubular dysfunction

Comments
Prolonged therapy (>2 yrs) or dose >5 mg/kd/day C/b vasoconstriction of afferent glomerular arterioles GFR magnesium reabsorption, uric acid excretion, K+ & H+secretion, and distal tubular acidosis. HCO3-, and hyperkalemia Glomerular or arteriolar thrombi, arteriolopathy, and interstitial fibrosis with tubular atrophy Vacuolization of PCT, giant mitochondria in tubular epithelial cells, single cell necrosis, and microcalcification of TammHorsfall protein in DCT

o Structural

Vasculopathy

Tubulopathy

Malignancy Skin cancers, Cervical cancer, Lymphoproliferative

Incidence appears to be a function of overall amount and duration

Event
Gastrointestinal Nausea, abdominal pain, diarrhea, vomiting, Hyperbilirubinemia, cholelithiasis

Comments
If serum bilirubin or transaminases rise to twice the normal value, a dose reduction of 25% is necessary

Neurologic Headaches, tremor, seizures, psychosis, paraesthesias, and sleep disturbance, Pseudotumor cerebri,

Decrease in high-energy phosphate metabolism and a reduction in intracellular concentrations of neurotransmitters

hypertension (S>140 or D>90 mm Hg)

Dose reduction of 25% to 50% or start CCBs amlodipine have vasodilating effect on afferent arteriole

Hyperlipidemia (hypertriglyceridemia )

Normalizes on discontinuation of drug

Event
Cutaneous Hypertrichosis, epidermal cysts, keratosis pilaris, acne, folliculitis, and sebaceous hyperplasia. Gingival hyperplasia

Comments
Cyclosporine modulates protein kinase C expression and translocation in hair epithelial cells and promotes proliferation of these cells Caused by fibrous hyperplasia and has been reported in up to 30% of patients on cyclosporine, with a higher incidence reported in children

Infections

Rare and seldom severe, treatment of the infection or withdrawal of the drug led to resolution Slight NC, NCr anemia Fatigue, lethargy, and flu-like symptoms are common joint pain and muscle aches in 10% to 40%

Other side effects

Patients should be instructed to attend their dentist at 6-month intervals National malignancy screening programs should be adhered to

Where possible Vaccination should take place before initiation of treatment

Investigation Full history

Details Previous infections: TB, hepatitis B/C; history of hypertension, kidney disease, liver disease, or malignancy; full medication history, which should be repeated at every subsequent visit

Blood pressure

Baseline (2 separate measurements, should be <140/90 mm Hg); taken again at weeks 2, 4, 6, and 8, then monthly

Physical examination

Actinic damage/cutaneous malignancies; herpes simplex; viral warts

Investigation
Serum creatinine

Details
Baseline (mean of 2 separate fasting measurements; if discrepancy of >10%, repeat again);taken again at weeks 2, 4, 6, and 8, then monthly

Blood urea nitrogen

Baseline and at weeks 2, 4, 6, and 8, then monthly

Complete blood cell count Potassium

Baseline, then monthly Baseline, then monthly

Bilirubin, liver enzymes

Fasting lipid profile Uric acid Magnesium Urinalysis

Baseline, then monthly

Baseline, then monthly Baseline, then monthly Baseline, then monthly Baseline, then monthly

Investigation Tuberculin test Glomerular filtration rate Screening Programs

Details Baseline After 1 y of continuous therapy Cervical, breast, and colon cancer screening as per national guidelines

Vaccinations

Annual pneumococcal and influenza vaccinations

o o o o o

Typically monitored in transplant patients to avoid toxicity Minimum of 0.5 mL ( cc) whole blood, collected in purple-top tube. Sample should not be centrifuged. Sample may be frozen or kept cold in refrigerator until analysis. Samples are stable for 30 days at -20C (frozen).

Trough or C0 level (samples are collected immediately before next scheduled dose) Low risk
0-6 m 150-250 ng/ml

Mod Risk
175-325 ng/ml

High risk
200-350 ng/ml

6-12 m

100-200 ng/ml

125-225 ng/ml

150-250 ng/ml

> 12 m

50-150 ng/ml

75-175 ng/ml

100-200 ng/ml

S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

Cyclosporin: C2 Level (two-hour sample)

< 6 months: 1000-1500 ng/ml > 6 months: 800-900 ng/ml

Little evidence from prospective studies to

support theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no short-term clinical benefit is seen.*

*Knight, S R. et al. Transplantation 2007 Jun; 83(12):1525-1535

o o o o

Crosses placental, category C drug in pregnancy Pregnancy registries show no increase in risk of teratogenicity, Although there were trends towards low birth weight and prematurity Excreted in breast milk

o o

Decreased bioavailability in children Children are less susceptible to cyclosporine-induced nephropathy than adults

o o

Use in psoriasis changed entire field of psoriasis research From that of a hyperproliferative, keratinocytedriven disorder to that of an immune-driven disease, Provided a way for biologic revolution in psoriasis. Useful in treatment of significant flares of cutaneous disease especially psoriasis and atopic dermatitis Bridging agent during induction of other maintenance agents.

o o

o o

Combination or rotational therapy can be used to minimize cumulative dosage and long-term side effects. Treatment for more than 1 year should be avoided where possible. Side effects are dose and duration dependent, reversible on discontinuation It is a drug that should be an integral part of our therapeutic armamentarium Provided that guidelines are closely followed.