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.

1. Apremilast
Dr Shinde Viraj Ashok
Junior Resident – 2
Department of Pharmacology
GMC Nagpur

2. Overview
Introduction
Pharmacodynamics
Pharmacokinetics
Therapeutic efficacy
Current status

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

5. • Associated with ↑ incidence of non melanoma &
melanoma skin cancer

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

11. Pharmacodynamics
 Effects on skin and other parameters

12. Effects on skin and other parameters
• QT not prolonged –when given in dosages of 50mg
twice daily

13. Pharmacokinetic
Peak plasma concentration – 2.5h
Absolute bioavailability – 73%
Bioavailabilty – Not affected by food
Linear pharmacokinetics
PPB – 68%
aVd – 87 L

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 +

23. Current status
Active psoriatic arthritis with
 Inadequate response
or to DMARDs
 Intolerance

24. References
• Drugs (2015) 75; Apremilast : A review in psoriasis and
psoriatic arthritis
• Harrison's Principles of Internal Medicine, 18e