cyclosporine - pharmacology, uses, side effects and monitoring guidelines

2. 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.

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

4. 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%

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

6. 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.

7. 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

8. Action on calcineurin / NFAT pathway

9. 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)

10. 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) .

11. o US FDA approved
› Psoriasis
› Severe Psoriasis
› Recalcitrant, treatment resistant Psoriasis
› Disabling Psoriasis
o Approved in other countries
› Psoriasis
› Atopic dermatitis

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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.

21. 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.

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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%

31. 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

32. 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

33. 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

34. 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

35. 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).

36. 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)

37.  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

38. 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

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

40. 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.

41. 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.