crisaborole the new topical treatment of atopic dermatitis.
it is used in patient with atopic dermatitis 2 years and more.
safe treatment for atopic dermatitis.
2. INTRODUCTION
Crisaborole is a novel oxaborole approved
for topical treatment of mild to moderate
atopic dermatitis in patients 2 years old
and older.
3. • Efficacious in-
–Improving disease severity
–Reducing the risk of infection
–Reducing the signs and symptoms
–Reducing the local inflammation in the skin
–Preventing further exacerbation of the
disease with a good safety profile.
4. • Currently under development as topical
treatment of psoriasis.
• Shown efficacy in treating inflammatory linear
verrucous epidermal nevus
5. Why crisaborole?
• Although chronic inflammatory skin diseases
such as atopic dermatitis and psoriasis can be
effectively treated with topical treatments, a
number of safety concerns warrant special
consideration.
6. • Topical corticosteroids (TCSs) and topical
calcineurin inhibitors (TCIs) are effective
treatment options for AD-
– Use of TCS on thin-skinned areas such as the face,
intertriginous areas, and genitals are limited by
potential adverse effects.
– TCIs are associated with application-site reactions
and contain a boxed warning citing cases of
malignancy
7. Therapy Adverse Event Malignancy Risk
Topical
Corticosteroi
ds
Epidermal atrophy;
telangiectasia;
tachyphylaxis;
systemic absorption
leading to HPA axis
suppression
Evidence-based: No
evidence of
immunosuppressive
malignancy
Topical
Calcineurin
Inhibitors
Irritation at application
site
Theoretical: topical dosing
can induce cancer in mice
at >40x maximum human
recommended dose.
Evidenced-based: No
evidence of
immunosuppressive
malignancy Skin
9. • In psoriasis, cutaneous irritation may develop
following treatment with topical retinoids and
vitamin D analogs
• Therefore, effective and well-tolerated topical
treatment alternatives that can be safely
applied to the face and other thin and
sensitive skin areas are needed for
inflammatory skin diseases such as atopic
dermatitis and psoriasis.
10.
11. • This compound 3 is a benzoxaborole which
was called AN2728 and PF-06930164 during
preclinical and clinical development.
• And now it is called crisaborole.
12. Structure
• A member of the class of benzoxaboroles that
is 5-hydroxy-1,3-dihydro-2,1-benzoxaborole in
which the phenolic hydrogen has been
replaced by a 4-cyanophenyl group.
13. • This lead to formation of Crisaborole, 5-(4-
cyanophenoy)-1,3-dihydro-1- hydroxy-[2,1]-
benzoxaborole
14. • The empirical formula is C14H10BNO3 and the
molecular weight is 251.1 g/mol.
• Crisaborole drug substance is freely soluble in
common organic solvents such as isopropyl
alcohol and propylene glycol, and insoluble in
water.
15. Mechanism of action
• Boron-based small molecules are potent
inhibitors of phosphodiesterase 4 (PDE4)
exerting broad-spectrum anti-inflammatory
activity.
• Intracellular PDE4 is an enzyme that converts
the intracellular second messenger 3'5'-cyclic
adenosine monophosphate (cAMP) into the
active metabolite 5’-AMP
16. • PDE4 predominantly found in keratinocyte
and immune cells, including—
– B cells,
– T cells,
– Neutrophils,
– Monocytes,
– Macrophages, and
– Eosinophils.
17.
18. • The inclusion of boron mimics the phosphate
in cAMP, allowing the drug to effectively target
the PDE4 and inhibit cAMP breakdown
19. • The resulting increase in cAMP activates
protein kinase A.
• This protein kinase negatively modulates
signaling pathways
– Nuclear factor-kB and
–T-cell signalling pathways
20. • This promote release of Th1 and Th2 cytokines
involved in initiating and sustaining
–Inflammation,
–Pruritus and
–Epidermal hyperplasia.
21.
22. • Benzoxaborole PDE4 inhibitors have been
shown in cell culture to suppress release of
tumor necrosis factor-alpha (TNFα),
interleukin23 (IL-23), IL-22, IL-17, IL-14, IL-13,
IL-4, and interferon-ɤ.
23. Pharmacokinetics: Absorption
• Topical application of this drug is useful as it
potentiates the localization of this drug in the
skin
• The use of boron chemistry enabled synthesis
of a low-molecular-weight compound (251
daltons), thereby facilitating effective
penetration of crisaborole through human
skin
24. • Topical administration of PDE4 inhibitors
allows rapid absorption into the skin, but
limits systemic exposure.
• Systemic concentrations of crisaborole were
reached by 8 days of twice-daily topical
administration.
25. • The small fraction of a crisaborole 2%
ointment dose that is systemically absorbed is
low , thus posses less risk for developing
systemic side effects.
27. Pharmacokinetics: Metabolism
• The small fraction absorbed systemically
undergoes extensive hepatic metabolism via
hydrolysis and subsequent oxidation to two
inactive metabolites.
• The major metabolite 5-(4-cyanophenoxy)-2-
hydroxyl benzylalcohol (metabolite 1), is
formed via hydrolysis.
28. • This metabolite is further metabolized into
downstream metabolites, among which 5-(4-
cyanophenoxy)-2-hydroxyl benzoic acid
(metabolite 2), formed via oxidation, is also a
major metabolite.
• Crisaborole does not produce clinically
significant induction or inhibition of
cytochrome P450 enzymes
33. Content of formulation
• Active ingredient: crisaborole(each gram
contains 20 mg crisaborole )
• Inactive ingredients: white petrolatum,
propylene glycol, mono- and di-glycerides,
paraffin, butylated hydroxytoluene, and
edetate calcium disodium.
34. Dosing
• Applied in a thin layer twice daily to affected
areas of the skin only
• Not for ophthalmic, oral, or intravaginal use.
35. Side effects
• Common :
– Application site pain(1% to 10%) present as
burning or stinging
• Less frequent:
– Contact urticaria ( <1%)
– Hypersensitivity reaction: Hypersensitivity should
be suspected in the event of severe pruritus,
swelling and erythema at the application site or at
a distant site.
36. • No evidence of mutagenic or clastrogenic
potential as well as altered effects on
fertility.
37. • No drug-related neoplastic findings were
noted at topical doses up to 7% crisaborole
ointment (2 times the Maximum
recommended human dose)
38. Drug Interaction Studies
• In vitro studies using human liver microsomes
indicated that under the conditions of clinical
use, crisaborole and metabolite 1 are not
expected to inhibit cytochrome P450 (CYP)
1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4.
39. • In vitro human liver microsomes studies for
metabolite 2 showed that it did not inhibit
activities of CYP2C19, 2D6, and 3A4; was a
weak inhibitor of CYP1A2 and 2B6; and a
moderate inhibitor of CYP2C8 and 2C9
40. • The most sensitive enzyme, CYP2C9, was
further investigated in a clinical trial using
warfarin as a CYP2C9 substrate. The results of
this study showed no drug interaction
potential.
41. Crisaborole in Pregnancy
• There is no available data in pregnant women
to inform the drug-associated risk for major
birth defects and miscarriage.
• No adverse developmental effects were
observed in pregnant rabbits with oral
administration of crisaborole.
42. Crisaborole in Breastfeeding
• There is no information available on
–the presence of crisaborole in human milk,
– the effects of the drug on the breastfed
infant, or
–the effects of the drug on milk production
after topical application of crisaborole to
women who are breastfeeding.
43. • Absorbed systemically
• Therefore, the developmental and health
benefits of breastfeeding should be
considered along with the mother’s clinical
need for crisaborole
44. Pediatric Use
• The safety and effectiveness of crisaborole
have been established in pediatric patients
age 2 years and older for topical treatment of
mild to moderate atopic dermatitis.
45. • The safety and effectiveness of EUCRISA in
pediatric patients below the age of 2 years
have not been established yet.
46. CONCLUSION
• The novel nonsteroidal anti-inflammatory
topical agent, crisaborole, can herald an new
era not only in treatment of atopic dermatitis
but also in treatment of psoriasis, vitiligo,
Inflammatory linear verrucous epidermal
nevus.
