Mechanism of Action of Apremilast (Otezla)

Introduction

Apremilast (Otezla) is an oral phosphodiesterase-4 (PDE4) inhibitor approved for psoriasis, psoriatic arthritis, and Behçet’s disease‑associated oral ulcers. By modulating intracellular signaling, it reduces inflammation and disease symptoms through balanced cytokine regulation.

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Step-by-Step Mechanism of Action

1. Inhibition of PDE4 enzyme
   Apremilast selectively inhibits PDE4 in immune cells, preventing breakdown of cyclic adenosine monophosphate (cAMP).
2. cAMP accumulation
   Elevated intracellular cAMP activates protein kinase A (PKA) and the transcription factor CREB to alter gene expression.
3. Pro-inflammatory cytokine suppression
   It decreases synthesis of TNF‑α, IL‑23, IL‑17, and IFN‑γ—key mediators in psoriasis and psoriatic arthritis.
4. Anti-inflammatory cytokine induction
   Levels of IL‑10, an anti-inflammatory cytokine, are increased.
5. Reduced inflammatory cell recruitment
   The net result is diminished migration and activation of inflammatory cells, reducing tissue damage and clinical symptoms.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral (delayed-release tablet)
Bioavailability	~73%
Time to Peak (Tmax)	~2–4 hours
Protein Binding	~68%
Metabolism	Extensive hepatic via CYP3A4, CYP1A2, CYP2A6
Half-life	~6–9 hours
Excretion	Urine (~58%), feces (~39%)

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Clinical Uses

• Moderate to severe plaque psoriasis
• Active psoriatic arthritis
• Oral ulcers in Behçet’s disease

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Adverse Effects

• Common: diarrhea, nausea, headache, upper respiratory infections, weight loss
• Rare: depression, mood changes
• Low risk: serious infections, malignancy

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Comparative Analysis

Drug	Target	Administration	Primary Indications
Apremilast	PDE4	Oral daily	Psoriasis, PsA, Behçet’s
Methotrexate	DHFR inhibitor	Oral/IM weekly	Psoriasis, PsA, RA
Biologics	TNF, IL‑17	Injectable	Moderate-to-severe disease

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MCQs

1. Apremilast inhibits which enzyme?
   a) PDE3 b) PDE4 c) PDE5 d) PDE6
   Answer: b) PDE4
2. What is the result of PDE4 inhibition?
   a) ↓ cAMP b) ↑ cAMP c) ↓ cGMP d) ↑ cGMP
   Answer: b) ↑ cAMP
3. Pro-inflammatory cytokine reduced by apremilast includes:
   a) IL‑2 b) TNF‑α c) IL‑4 d) IL‑1β
   Answer: b) TNF‑α
4. Which cytokine is increased?
   a) IL‑17 b) IFN‑γ c) IL‑23 d) IL‑10
   Answer: d) IL‑10
5. Common GI side effects are:
   a) Constipation b) Diarrhea, nausea c) Pancreatitis d) Gallstones
   Answer: b) Diarrhea, nausea
6. Route of elimination includes:
   a) Renal and fecal b) Pulmonary c) Biliary only d) Sweat
   Answer: a) Renal and fecal
7. Half-life of apremilast is:
   a) 2–3 hrs b) 6–9 hrs c) 12–16 hrs d) 24 hrs
   Answer: b) 6–9 hrs
8. Primary therapeutic uses include:
   a) Hypertension b) Psoriasis, PsA, Behçet’s c) Diabetes d) Asthma
   Answer: b) Psoriasis, PsA, Behçet’s
9. Apremilast affects CREB via:
   a) ↓ cAMP b) ↑ cAMP c) ↓ cGMP d) ↑ cGMP
   Answer: b) ↑ cAMP
10. Compared to biologics, apremilast advantage is:
    a) Injectable administration b) Oral dosing c) Higher cost d) More side effects
    Answer: b) Oral dosing

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FAQs

1. Can apremilast be used with methotrexate?
Yes—combination therapy is common in psoriatic arthritis for better disease control.

2. How fast do symptoms improve?
Most patients see improvement within 2–4 weeks, with continued benefit over months.

3. Does it require lab monitoring?
No regular lab tests needed, unlike methotrexate or biologics.

4. Is weight loss permanent?
Usually mild and stabilizes over time; monitor if significant.

5. Can it worsen mood disorders?
Rarely—patients with depression history should be monitored for mood changes.

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References

• Apremilast prescribing information (FDA)
• DrugBank: Apremilast mechanisms
• StatPearls: Apremilast in psoriasis and psoriatic arthritis
• PubMed review: PDE4 inhibition and inflammatory disease