Apremilast is a small molecule inhibitor of phosphodiesterase 4 approved for treatment of moderate to severe plaque psoriasis and active psoriatic arthritis. It works by downregulating inflammatory immune mediators. Pharmacokinetically, it has good oral bioavailability and undergoes extensive metabolism. Clinical trials showed apremilast improved signs and symptoms of psoriasis and psoriatic arthritis over both short and long term use. The most common side effects are diarrhea, upper respiratory tract infection, and nausea. Apremilast is approved in Europe and the US for patients with psoriasis or psoriatic arthritis with inadequate response or intolerance to other systemic therapies.
3. Definition
• Chronic inflammatory skin disorder clinically
characterized by erythematous, sharply demarcated
papules and rounded plaques, covered by silvery
micaceous scale
Psoriasis
4. Standard treatment of
psoriasis
• Type, location & extent of disease
• Localized , plaque type psoriasis - Midpotency topical
glucocorticoids
• Long-term use is often accompanied by
• Loss of effectiveness
• Atrophy of the skin
• Topical vitamin D analogue (calcipotriene) & retinoid
(tazarotene) - Efficacious
6. • Methotrexate
Severe or refractory plaque type of psoriasis
Effective agent in patients with psoriatic arthritis
• Synthetic retinoid - acitretin
Drug of choice in psoriasis with AIDS
Teratogenicity limits its use
• Oral glucocorticoids –
Should not be used for treatment of psoriasis due to potential
for developing life-threatening pustular psoriasis when
therapy is discontinued
7. • Cyclosporine - Very effective in the treatment of
psoriasis
• Psoriasis - T cell–mediated disorder - has directed
therapeutic efforts to immunoregulation
• Attention is currently directed towards development of
biologic agents with more selective immunosuppressive
properties and better safety profiles
8. Apremilast
• Small molecule inhibitor of
phosphodiesterase(PDE)- 4 (main PDE in
inflammatory cells)
• Results in down regulation of immune mediators
9. Pharmacodynamics
Selective inhibitor of Phosphodiesterase – 4
Effects on immune mediators –
• Inhibited production of (in vitro & in animals)
• Chemokines ( CXCL9 , CXCL10)
• Interleukins (IL2 , 5 ,IL 12 A, IL 13)
• Cytokines like interferon α & γ, TNF α and GM- CSF
• Adaptive immune mechanism minimally affected –
No significant effect on B cell immunoglobulin
production
10. Effects on immune mediators
• Exploratory analysis of Phase 3 study –
PALACE 1 - Psoriatic arthritis patients
significantly (p < 0.05 ) reduced circulating
levels proinflammatory innate Th 1 immunity
components relative to placebo over 4 – 24
weeks of therapy
14. Pharmacokinetic
• Undergoes extensive metabolism
• Oxidative metabolism – cytochrome P 450 enzymes
• Glucuronidation
• Non CYP driven hydrolysis
Avoid coadministration with CYP
inducers like
Carbamazepine , phenytoin ,
phenobarbital , rifampicin
15. Pharmacokinetic
Main circulating
component – after
apremilast
administration
Unchanged drug
45%
Inactive
glucuronide
conjugate of O
demethylated
apremilast
Excretion
Urine – 58%
Faeces – 39%
Terminal elimination
half life – 6 - 9h
16. Pharmacokinetic
• Hepatic impairment – No dosage
adjustments
• Mild to moderate renal impairment –
No dosage adjustment
• Dosages reduction – Creatinine
clearance ‹ 30 ml/min
Special
patient
population
17. Therapeutic efficacy
Psoriasis
Short term treatment
After 16 weeks –
More apremilast than placebo –
Achieved Psoriasis Area and Severity Index(PASI)
- 75 or PASI – 50 response in ESTEEM trials
18. • Long term treatment
After 32 weeks –
Apremilast responders re-randomised to apremilast
maintained PASI response at 52 week
Less than quarter of apremilast responders re-
randomised to placebo maintained PASI response
19. Therapeutic efficacy
Psoriatic arthritis (PsA)
Short term treatment –
Apremilast 30mg twice daily for 16 weeks– improved
signs and symptoms of PsA.
PALACE 1 reported significantly (0.007) greater ACR 20
response rate in apremilast group than placebo recepients
20. Therapeutic efficacy
Long term treatment –
PALACE 1, 2 &3 –
At 52 weeks- Improvements in enthesitis & dactylitis
At 104 weeks - Benefits of apremilast therapy on PsA in
signs & symptoms, disease activity & physical function
21. Adverse effects
• Most common adverse effects 30mg twice daily
Diarrhoea ,URTI &Nausea up to 52weeks
URTI & nasopharyngitis >52 – 104 weeks
• Apremilast recipients – Experience weight loss
Underweight patients initiating apremilast - Regular bodyweight
monitoring
Discontinuation if clinically significant weight loss occurs
22. Current status
Oral apremilast 30mg twice daily – Approved in Europe &
USA for treatment of
Moderate to severe chronic plaque psoriasis
Non responders
or
Contraindication + to systemic therapies
or
Intolerannce +
24. References
• Drugs (2015) 75; Apremilast : A review in psoriasis and
psoriatic arthritis
• Harrison's Principles of Internal Medicine, 18e
Notas do Editor
and have largely replaced other topical agents such as coal tar, salicylic acid, and anthralin
Ultraviolet light, natural or artificial - effective therapy for widespread psoriasis.
PDE4 hydrolyzes cyclic adenosine monophosphate (cAMP) to inactive adenosine monophosphate (AMP). Inhibition of PDE4 blocks hydrolysis of cAMP, thereby increasing levels of cAMP within cell
to systemic therapies including cyclosporine, methotrexate or phototherapy with psoralen plus ultraviolet A