Cyclosporine in dermatology


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cyclosporine - pharmacology, uses, side effects and monitoring guidelines

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Cyclosporine in dermatology

  1. 1. o 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.
  2. 2. › Cyclic polypeptide › Consist of 11 amino acids › Produced as a metabolite by Beauveria nivea.
  3. 3. Pharmacokinetics Absorption and bioavailability • Before meal higher absorption • Widely distributed • Ideal body weight should be used to calculate dose Elimination First-order kinetics Peak levels (hr) Bioavailabl e (%) 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 hepatobilia ry Renal 6%
  4. 4. o Sandimmune (cyclosporine, USP) o Gengraf (cyclosporine, USP – Modified) o Neoral (cyclosporine, USP – Microemulsion)
  5. 5. 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.
  6. 6. 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
  7. 7. Action on calcineurin / NFAT pathway
  8. 8. 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)
  9. 9. 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) .
  10. 10. o US FDA approved › Psoriasis › Severe Psoriasis › Recalcitrant, treatment resistant Psoriasis › Disabling Psoriasis o Approved in other countries › Psoriasis › Atopic dermatitis
  11. 11. Disease CsA dose Duration of Rx Response Time to relapse after discontinued Other drugs Comm ents 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
  12. 12. Disease CsA dose Duratio n of treatme nt Response Time to relapse after discontinued Other drugs Comments Psoriatic arthritis 3-4 mg/kg/da y, max 5 mg/kg/da y 6-12 mos Very good 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 Atopic dermatitis 2.5-3 mg/kg/da y, max 5 mg/kg/da y 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 gangrenosu m 5 mg/kg/da y >6 mos Excellent Methylprednisolo ne (0.5-1 mg/kg/day, or pulse treatment 1 g/day for 1-5 days) usually given concurrently
  13. 13. 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 severe Cetirizine 10 mg/day, occasionally concurrently Used as a steroid sparing agent or in cases refractory to corticosteroids
  14. 14. 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
  15. 15. Disease CsA dose Duration of treatment Response Time to relapse after discontinued Other drugs Comments Epidermolysis bullosa acquisita 4-5 mg/kg/d ay 1-24 mos Good, but better treatment options available Prednisone, u sually 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
  16. 16. 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
  17. 17. Disease CsA dose Duration of treatment Response Time to relapse after discontinued Other drugs Comments Severe alopecia areata 5 mg/kg/da y 2-12 mos Mixed 33%-86% with >70% hair regrowth, 76% with maintained hair regrowth at 12 mos follow- up 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 Ds. 1.2-3.4 mg/kg/da y 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/da y Good Prednisolone, broad spectrum antibiotics Scleroderma May potentially worsen hypertension or renal disease associated with systemic sclerosis
  18. 18. o Pemphigoid o Linear IgA bullous dermatosis o Lupus erythematosus o Granuloma annulare o Sarcoidosis o Kimura’s ds. o Morphea o Papular erythroderma of ofuji o Purpura pigmentosa chronica o Reiter’s syndrome o Scleromyxedema o Sezary’s syndrome o Mycosis fungoides
  19. 19. o 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.
  20. 20. 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.
  21. 21. 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
  22. 22. o Drugs that inhibit or stimulate cytochrome P450 o Nephrotoxic drugs should be avoided o A full drug history should be taken at every visit
  23. 23. o Calcium channel blockers Diltiazem, nicardipine, verapamil, and mibefradil o Antifungals Ketoconazole > itraconazole > Fluconazole, and voriconazole o Antibiotics Erythromycin, clarithromycin, and josamycin, Doxycycline, Gentamicin and tobramycin, Ticarcillin, Ciprofloxacin o Oral contraceptives o Amiodarone o Cimetidine o Protease inhibitors o Warfarin o Grapefruit juice o SSRIs (sertraline) By other mechanism o Methylprednisolone o Allopurinol o Thiazide diuretics o Furosemide
  24. 24. o Anticonvulsants (carbamazepine, phenobarbitone, phenytoin, and valproate) o Rifampicin o Rifabutin o Isoniazid o Griseofulvin o Probucol o Ticlopidine o Nafcillin o Octreotide o Orlistat o Bexarotene
  25. 25. 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
  26. 26. o Are leading cause of its limited use in dermatology. o Depend on dose and duration of therapy o Reversible on discontinuation, o Structural renal abnormalities may be persistent. o Mitochondrial dysfunction (ion channel regulation) o Inhibition of immunophilins may play a role
  27. 27. Event Comments •Renal dysfunction o 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 Incidence appears to be a function of overall amount and duration
  28. 28. Event Comments Gastrointestinal Nausea, abdominal pain, diarrhea, vomiting, Hyperbilirubinemia, cholelithiasis 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
  29. 29. Event Comments Cutaneous Hypertrichosis, 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 anemia Fatigue, lethargy, and flu-like symptoms are common joint pain and muscle aches in 10% to 40%
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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).
  35. 35. 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)
  36. 36.  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
  37. 37. 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
  38. 38. o Decreased bioavailability in children o Children are less susceptible to cyclosporine-induced nephropathy than adults
  39. 39. 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.
  40. 40. 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.