cyclosporine in dermatology
DESCRIPTION
cyclosporine - pharmacology, uses, side effects and monitoring guidelinesTRANSCRIPT
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