SEMINAR PRESENTATION

CYCLOSPORINE IN DERMATOLOGY

MODERATOR: Dr AMIT K. MALHOTRA

History

o 1970, isolated as narrow antifungal from Tolypocladium inflatum Gams

o 1976, found to be a potent immunosuppressiveo 1983, FDA approval for transplant rejection. o 1997, FDA approval for Rx of psoriasiso Approved for atopic dermatitis in other

countries.

Structure

› 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

EliminationFirst-order kinetics

Peak levels (hr)

Bioavailable (%)

Protein binding (%)

Half-life (hr)

Metabolism Excretion

2-4 30 90 5-18 CYP3A4 and CYP3A5 in liver Efflux p-glycoprotein pump (PGP), in GI tract and liver

Primarily hepatobiliaryRenal 6%

› Diff erent preparation are not equivalent

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

Advantages of CsA Microemulsion formulation

o Twice the bioavailability

o Less intraindividual and interindividual variability

o Reduced time (more than 30 percent) to maximal concentration (Tmax)

o Absorption and drug levels are less susceptible to effects of food (particularly fatty foods),

o Not dependent upon bile salts for absorption.

MOA

o 1. Action on the calcineurin / NFAT pathway

o 2. Action on JNK and p38 signaling pathways

o 3. Action by Induction of TGF-b

Action on calcineurin / NFAT pathway

Action on JNK and p38 signaling pathways

o 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)

Action by Induction of TGF-b

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)

o TGF-b is known to stimulate cells to increase their extracellular matrix ECM composition

o Decreases production of ECM-degrading proteases, o Thereby inducing a profibrogenic state

(Massague,1990) . o TGF-b produced by CsA administration directly promotes cancer progression (Hojo et al., 1999) .

Clinical uses of cyclosporine and regimens 

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

o Approved in other countries› Psoriasis› Atopic dermatitis

Disease CsA dose Duration of Rx

Response Time to relapse after discontinued

Other drugs

Comments

Psoriasis 12-16 wks, 12 mos maximum

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

A. Intermittent short-term therapy

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

B. Rescue therapy

5 mg/kg/day for 12-16 wks for flaring of disease

C. Long term therapy

<5 mg/kg/day for up to 1 y; reducing dose to lowest effective

D. Combination therapy

Corticosteroids, anthralin, or vitamin D3 analogues for an

improved response. MTX, fumaric acid esters, and mycophenolate mofetil in severe cases

E. Rotational therapy

Can minimize CsA toxicity

Disease CsA dose

Duration of treatment

Response Time to relapse after discontinued

Other drugs

Comments

Psoriatic arthritis

3-4 mg/kg/day, max 5 mg/kg/day

6-12 mos Very good MTX 15 mg/wk, occasionally

50% reduction in joint complaints required 24 wks of CsA monotherapy, CsA-MTX combination therapy given to patients with partial MTX response

Atopic dermatitis

2.5-3 mg/kg/day, max 5 mg/kg/day

12-16 wks, 12 mos max

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

Used for short treatment of severe, AD that cannot be controlled with topical therapy. Approved for this in Europe and UK

Pyoderma gangrenosum

5 mg/kg/day

>6 mos Excellent Methylprednisolone (0.5-1 mg/kg/day, or pulse treatment 1 g/day for 1-5 days) usually given concurrently

Disease CsA dose Duration of treatment

Response Time to relapse after discontinued

Other drugs

Comments

Dyshidrotic eczema

2.5-3 mg/kg/day

6 wks, up to 16 wks

Equivalent 77% of patients continued to have a 54% improvement at 1 y

CsA equivalent to BDP cream

Behçet disease

5 mg/kg/day >6 mos Very good Prednisone, occasionally Used for refractory eye disease, topical steroid–resistant 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 severeCetirizine 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 mg/kg/day, maintenance dose 2 mg/kg/day

>8 mos Mixed Used in erythrodermic classic adult and erythrodermic juvenile PRP

Dermato -myositis

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

Very good Prednisone 40 mg/day Used in cases not responsive to prednisone combined with MTX or azathioprine. Effective for lung and esophageal involvement

Pemphigus vulgaris

1-3 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

Prednisone, usually given concurrently

Used as a steroid sparing agent

Disease CsA dose

Duration of treatment

Response Time to relapse after discontinued

Other drugs Comments

Epidermolysis bullosa acquisita

4-5 mg/kg/day

1-24 mos Good, but better treatment options available

Prednisone, usually given concurrently

Used as steroid sparing agent

Photodermatoses

A. Chronic actinic dermatitis

4-4.5 mg/kg/day

Good

B. Polymorphic light eruption

3-4 mg/kg/day

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

Good

C. Solar urticaria

4.5 mg/kg/day

Short courses during summer months

Flares once cyclosporine discontinued

Disease CsA dose

Duration of treatment

Response Time to relapse after discontinued

Other drugs

Comments

Lichen planopilaris

3-5 mg/kg /day

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

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

Prurigo nodularis

3.5-4 mg/kg /day

6-9 mos Good

Lichen planus

3-4.5 mg/kg /day

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

Response Time to relapse after discontinued

Other drugs Comments

Severe alopecia areata

5 mg/kg/day

2-12 mos Mixed 33%-86% with >70% hair regrowth, 76% with maintained hair regrowth at 12 mos follow-up

Methylprednisolone (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-HaileyDs.

1.2-3.4 mg/kg/day

6-8 mos Good Acitretin 10 mg/day, occasionally

Eosinophilic pustular folliculitis

100-150 mg/day

2-12 wks Good

Hidradenitis suppurativa

4-4.5 mg/kg/day

Good Prednisolone, broad spectrum antibiotics

Scleroderma May potentially worsen hypertension or renal disease associated with systemic sclerosis

OTHER OFF-LABEL USES

o Pemphigoido Linear IgA bullous dermatosiso Lupus erythematosuso Granuloma annulareo Sarcoidosiso Kimura’s ds.o Morpheao Papular erythroderma of ofujio Purpura pigmentosa chronica o Reiter’s syndrome o Scleromyxedemao Sezary’s syndromeo Mycosis fungoides

Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony stimulating factor.Jarrett P, Rademaker M, Havil, Pullon H

o Department of Dermatology, Health Waikato, New Zealand.

o Abstracto 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.

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.

Contraindications 

o ABSOLUTE• Uncontrolled 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 RELATIVE • Age <18 Yr or >64 Yr• Controlled

hypertension• Planning to receive

live attenuated vaccination

• Active infection or immunodeficiency

• Concomitant phototherapy, MTx or other immunosuppressive

• Pregnancy or lactation• Unreliable patient

Drug interactions

o Drugs that inhibit or stimulate cytochrome P450

o Nephrotoxic drugs should be avoidedo A full drug history should be taken at

every visit

Drugs that inhibit the cyt P450 system, leading to a higher concentration of cyclosporine

o Calcium channel blockers Diltiazem, nicardipine,

verapamil, and mibefradilo Antifungals

Ketoconazole > itraconazole > Fluconazole, and voriconazole

o Antibiotics Erythromycin,

clarithromycin, and josamycin, Doxycycline, Gentamicin and tobramycin, Ticarcillin, Ciprofloxacin

o Oral contraceptiveso Androgen steroids

o Amiodaroneo Cimetidineo Protease inhibitors o Warfarino Grapefruit juiceo SSRIs (sertraline) 

By other mechanismo Methylprednisoloneo Allopurinolo Thiazide diureticso Furosemide

Drugs that stimulate the cyt P450 system, leading to a lower

cyclosporine level

o Anticonvulsants (carbamazepine, phenobarbitone, phenytoin, and valproate) 

o Rifampicin o Rifabutino Isoniazido Griseofulvin

o Probucolo Ticlopidineo Nafcillin o Octreotideo Orlistato Bexarotene

Nonmetabolic Interactions With CsA

Drug Type Comments Nephrotoxic agents

NSAIDs Vancomycin Ganciclovir Aminoglycosides

Monitor renal function NSAIDs may have increased nephrotoxicity

with hepatic impairment

Potassium-sparing diuretics Hyperkalemia has been reported

Antacids 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

Side effect profile

o Are leading cause of its limited use in dermatology.

o Depend on dose and duration of therapyo Reversible on discontinuation, o Structural renal abnormalities may be

persistent.o Mitochondrial dysfunction (ion channel

regulation) o Inhibition of immunophilins may play a role

Event Comments

•Renal dysfunctiono Functional

Vascular dysfunction

Tubular dysfunction

o Structural Vasculopathy 

Tubulopathy 

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 Tamm–Horsfall protein in DCT

Malignancy Skin cancers,

Cervical cancer, Lymphoproliferative disorders

Incidence appears to be a function of overall amount and duration

Event Comments

GastrointestinalNausea, abdominal pain, diarrhea, vomiting, Hyperbilirubinemia, cholelithiasis

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

NeurologicHeadaches, 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 CommentsCutaneousHypertrichosis, epidermal cysts, keratosis pilaris, acne, folliculitis, and sebaceous hyperplasia.

Cyclosporine modulates protein kinase C expression and translocation in hair epithelial cells and promotes proliferation of these cells

Gingival hyperplasia 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

Other side effects  Slight NC, NCr anemiaFatigue, lethargy, and flu-like symptoms are commonjoint pain and muscle aches in 10% to 40% 

Monitoring 

o Patients should be instructed to attend their dentist at 6-month intervals

o National malignancy screening programs should be adhered to

o Where possible Vaccination should take place before initiation of treatment

Monitoring 

Investigation Details

Full history 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 Details

Serum creatinine 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 Baseline, then monthly

Potassium Baseline, then monthly

Bilirubin, liver enzymes Baseline, then monthly

Fasting lipid profile Baseline, then monthly

Uric acid Baseline, then monthly

Magnesium Baseline, then monthly

Urinalysis Baseline, then monthly

Investigation Details

Tuberculin test Baseline

Glomerular filtration rate After 1 y of continuous therapy

Screening Programs Cervical, breast, and colon cancer screening as per national guidelines

Vaccinations Annual pneumococcal and influenza vaccinations

Cyclosporine serum concentrations 

o Typically monitored in transplant patients to avoid toxicity

o Minimum of 0.5 mL ( ½ cc) whole blood, collected in purple-top tube.

o Sample should not be centrifuged.o Sample may be frozen or kept cold in

refrigerator until analysis.o Samples are stable for 30 days at -

20°C (frozen).

Monitoring

Low risk Mod Risk High risk

0-6 m 150-250 ng/ml 175-325 ng/ml 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.

Trough or C0 level (samples are collected immediately before next scheduled dose)

Monitoring

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

Pregnancy and Lactation 

o Crosses placental, category C drug in pregnancy

o Pregnancy registries show no increase in risk of teratogenicity,

o Although there were trends towards low birth weight and prematurity

o Excreted in breast milk

Pediatric use 

o Decreased bioavailability in childreno Children are less susceptible

to cyclosporine-induced nephropathy than adults

Conclusion 

o Use in psoriasis changed entire field of psoriasis research

o From that of a hyperproliferative, keratinocyte-driven disorder to that of an “immune-driven” disease,

o Provided a way for biologic revolution in psoriasis.

o Useful in treatment of significant flares of cutaneous disease — especially psoriasis and atopic dermatitis

o Bridging agent during induction of other maintenance agents.

o Combination or rotational therapy can be used to minimize cumulative dosage and long-term side effects.

o Treatment for more than 1 year should be avoided where possible.

o Side effects are dose and duration dependent, reversible on discontinuation  

o It is a drug that should be an integral part of our therapeutic armamentarium

o Provided that guidelines are closely followed.

THANKS