Topical Immunosuppressants

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Topical Immunosuppressants

• Bindi M. Nikhar, M.D., FAAP
• Division of Dermatologic and Dental Drug
  Products, ODE V

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TOPICAL IMMUNOSUPPRESSANTS

• Newest pharmacological class for AD
• Introduced in this decade
• Direct immunosuppressive action in diseases with
  an immunological basis
• 2 currently FDA approved products
• Tacrolimus (FK506) (trade name Protopic)
• Pimecrolimus (SDZ ASM 981) (trade name Elidel)

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Background

• Tacrolimus ointment approved on 12/08/2000, 0.03
  ointment approved for children 2 to 15 years,
  0.1 ointment approved for adults.
• Indication in both age groups is short and
  intermittent long term therapy of patients with
  moderate to severe AD.
• Systemic Tacrolimus (Prograf) first introduced
  for prevention of allograft rejection, now used
  in kidney, liver and heart transplantation

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Background (contd)

• Elidel cream 1 approved on 12/13/2001.
• Indicated for patients 2 years of age and older
  for short and intermittent long term therapy in
  the treatment of mild to moderate atopic
  dermatitis.
• Both drugs not approved for use in children less
  than 2 years of age.
• Systemic absorption can take place in both adult
  and pediatric age groups from the topical
  application of both drugs.
• Currently, the effects of topical
  immunosuppressants on the developing immune
  system are unknown.

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Pharmacokinetic (PK) studies for Tacrolimus

• Pooled results from 2 PK studies in 49 adult
  moderate-severe AD patients indicate that
  tacrolimus is absorbed after the topical
  application of 0.1 Protopic ointment.
• Peak tacrolimus levels ranged from undetectable
  to 20 ng/ml after single or multiple doses of
  0.1 Protopic ointment, 45 out of the 49 patients
  had peak concentrations less than 5 ng/ml.

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Pharmacokinetic studies for Tacrolimus (contd)

• A PK study of 0.1 Protopic ointment in 20
  pediatric AD patients (ages 6-13 years), showed
  peak tacrolimus concentrations below 1.6 ng/ml in
  all patients.
• Absolute bioavailability of topical tacrolimus is
  unknown.
• Using iv historical data for comparison, the
  bioavailability of tacrolimus from Protopic in AD
  patients is lt 0.5.
• Lowest tacrolimus blood level at which systemic
  effects can be observed is not known.

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Pharmacokinetic studies for Pimecrolimus

• In adults treated for AD with 1362 BSA
  involvement for periods up to a year, detectable
  pimecrolimus blood concentrations were lt 2 ng/ml
  (LOQ lt0.5 ng/ml).
• In 26 pediatric patients between 2-14 years with
  AD (20-69 BSA involvement) who had b.i.d.
  application for 3 weeks, blood concentrations of
  pimecrolimus were lt 3 ng/ml (LOQ lt 0.5 ng/ml)

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Pharmacokinetic studies for Pimecrolimus (contd)

• 20 out of 23 children investigated had at least
  one detectable blood level as compared to adults
  (13 out of 25 investigated) over a 3 week period.
  
• In 22 pediatric patients aged 3 to 23 months with
  10-92 BSA involvement, a higher proportion of
  blood levels ranging from 0.1 to 2.6 ng/ml (LOQ
  0.1 ng/ml) was seen.

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Pharmacokinetic studies for Pimecrolimus (contd)

• This increase may be due to larger surface area
  to body mass ratio seen in younger subjects.
• A higher incidence of upper respiratory
  symptoms/infections was also seen in the 3-23
  months age group relative to the older age group
  in PK studies.
• A causal relationship between these findings and
  Elidel use cannot be ruled out.

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Pharmacokinetics (contd)

• Some factors leading to higher systemic levels
  include
• Higher body surface area
• Younger age groups, especially the 3 to 23 month
  age groups as seen with pimecrolimus, this may be
  due to larger surface area to body mass ratio
  (this age group has not had pharmacokinetic
  testing for tacrolimus levels)
• Reduced skin barrier function eg. Nethertons
  syndrome

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Pediatric clinical studies

• Use of Protopic 0.03 ointment was studied in
  children 2-15 years of age by conducting 2 Phase
  3 studies.
• In these studies, varicella zoster and
  vesiculobullous rash were seen more frequently in
  patients treated with Protopic ointment 0.03,
  compared to vehicle.

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Pediatric clinical studies (contd)

• Elidel cream 0.1 was studied in infants 3-23
  months of age and in children 2-17 years of age.
• In the 2-17 years age group, nasopharyngitis,
  influenza, viral infections, pyrexia ,cough,
  headache, eczema herpeticum were increased over
  vehicle in the 1 year safety study.

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Pediatric clinical studies (contd)

• In the 3-23 months short term (6 week) infant
  study, pyrexia, URI, nasopharyngitis,
  gastroenteritis, otitis media, diarrhea seen more
  frequently compared to vehicle. The adverse event
  incidence for those in the open label phase of
  this study who switched over to Elidel cream from
  vehicle approached the incidence of those
  patients who remained on the cream.

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Pediatric clinical studies (contd)

• In the 6 month infant study safety data, adverse
  events occurring more frequently in the Elidel
  cream group compared to vehicle included pyrexia,
  URI, cough, vomiting, hypersensitivity, rhinitis,
  viral rash, rhinorrhea, and wheezing.

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Indications for use (Second-line)

• Both Protopic and Elidel are indicated for
  patients in whom the use of alternative,
  conventional therapies are deemed inadvisable
  because of potential risks, or in the treatment
  of patients who are not adequately responsive to
  or are intolerant of alternative, conventional
  therapies

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Proposed Mechanisms of Action

• Both Tacrolimus and Pimecrolimus inhibit
  T-cell activation by binding to the same
  cellular receptor, the FK-binding protein (FKBP)
  or macrophilin-12.
• The tacrolimus/pimecrolimus-FKBP complex
  further binds to calcineurin, which is an enzyme
  vital for early activation of both T helper cell
  types 1 and 2.

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Adverse Effects of Topical Immunosuppressants

• Local (Application site)
• Burning
• Pruritus
• Erythema
• Irritation
• Edema
• Urticaria

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Adverse effects of Topical Immunosuppressants
(contd)

• Systemic
• Pyrexia
• Upper and lower respiratory tract infection
• Nasopharyngitis
• Viral skin rashes eg. molluscum contagiosum,
  herpes simplex, herpes zoster, eczema herpeticum
• Influenza

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Adverse effects of Topical Immunosuppressants
contd

• Systemic side effects contd
• Otitis media
• Gastroenteritis, vomiting, diarrhea
• Streptococcal pharyngitis, staphylococcal
  infection
• Skin infection NOS
• Lymphadenopathy - In absence of a clear etiology
  or in the presence of acute infectious
  mononucleosis, discontinuation recommended. Close
  monitoring required.

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Adverse effects of Prograf

• Patients receiving Prograf are at an increased
  risk of developing lymphomas and other
  malignancies, particularly of the skin. The risk
  appears to be related to the intensity and
  duration of immunosuppression. A
  lymphoproliferative disorder (LPD) related to
  Epstein-Barr virus infection has been reported in
  immunosuppressed patients. The risk of LPD
  appears greatest in young children who are at
  risk for primary EBV infection while
  immunosuppressed.

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Potential long-term adverse effects of topical
immunosuppressants

• Increased incidence of malignancies in animal
  studies with topical tacrolimus(T) and
  pimecrolimus (P)
• Lymphomas P T
• Follicular cell adenomas P
• Skin tumors (with concurrent UV radiation
  exposure) P T

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Potential long-term adverse effects (contd)

• Since systemic use of calcineurin inhibitors
  is associated with formation of lymphomas and
  skin malignancies, low systemic exposure from
  topical calcineurin inhibitors over a course of
  time leading to a cumulative dose effect may lead
  to melanomas, non-melanoma skin cancers,
  Hodgkins and Non-Hodgkins lymphomas

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Concerns about long term side effects

• Children from the age of 2 years and upwards
  (with off- label use expected in even younger
  children) will be using these medications on a
  short or intermittent long term basis
• About one third of children with moderate-severe
  AD may continue to use these drugs into teenage
  and adult years, thereby having a long duration
  of exposure.

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Concerns about long term side effects (contd)

• Currently, we do not have long term safety data
  on either Tacrolimus or Pimecrolimus.
• Postmarketing evaluation of topical
  immunosuppressants is needed to evaluate this
  potential risk. Means of setting up these
  prospective studies need to be discussed.