What is Promacta (eltrombopag)?

Promacta (Eltrombopag): A Thrombopoietin Receptor Agonist

Promacta (eltrombopag) is an oral thrombopoietin receptor agonist that stimulates platelet production by activating the thrombopoietin receptor (cMpl) on megakaryocytes, leading to increased platelet counts in patients with thrombocytopenia. 1

Mechanism of Action

Eltrombopag works by:

• Binding to the transmembrane domain of the human thrombopoietin receptor (cMpl)
• Initiating signaling cascades that induce proliferation and differentiation of megakaryocytes
• Increasing platelet production through the JAK/STAT pathway, similar to endogenous thrombopoietin 1, 2

FDA-Approved Indications

Eltrombopag is FDA-approved for:

1. Chronic Immune Thrombocytopenia (ITP):

   • For patients who have had insufficient response to corticosteroids, immunoglobulins, or splenectomy 3
   • Response rates of 70-80% in clinical trials 4, 5

2. Thrombocytopenia in Chronic Hepatitis C:

   • To allow initiation and maintenance of interferon-based therapy 6
   • Increases platelet counts to sufficient levels in 95% of patients with baseline thrombocytopenia 6

3. Severe Aplastic Anemia (not detailed in the provided evidence)

Pharmacokinetics

• Oral administration with peak concentration occurring 1.5-5.5 hours (fasting) or 1.0-8.0 hours (fed) 1
• Half-life: 21-32 hours in healthy subjects, 26-35 hours in ITP patients 1
• Extensively metabolized through CYP1A2 and CYP2C8 pathways 1
• Predominantly excreted via feces (59%) and urine (31%) 1
• Higher exposure (50-55%) in patients of East/Southeast Asian ancestry 1

Dosing

• Initial dose: 50 mg once daily for adults with ITP 5
• Reduced initial dose (25 mg) for patients of East/Southeast Asian ancestry 1
• Should be taken on an empty stomach (1 hour before or 2 hours after meals) 5
• Dose adjustments based on platelet response, not exceeding 75 mg daily 5
• Response typically observed within 1-2 weeks of treatment initiation 5

Efficacy

In clinical trials for ITP:

• 59-70% of patients achieved platelet counts ≥50,000/μL (vs. 11-16% with placebo) 7
• Reduced bleeding events compared to placebo 7
• Long-term remission rate of approximately 30% 5

Safety Considerations

Common Adverse Events

• Nausea, diarrhea, upper respiratory tract infection, vomiting 4
• Increased alanine aminotransferase, myalgia, urinary tract infection 4

Important Risks

1. Hepatotoxicity:

   • Requires regular monitoring of liver function tests 5
   • Boxed warning related to risk of hepatotoxicity 8

2. Thromboembolic events:

   • Risk of 2% in clinical trials 5
   • Use with caution in patients with pre-existing thrombotic risk factors 4

3. Bone marrow reticulin formation:

   • Typically mild, asymptomatic, and reversible upon treatment interruption 4
   • Bone marrow examination should be considered if treatment failure or new cytopenia develops 5

4. Rebound thrombocytopenia:

   • Can occur after discontinuation 4
   • Platelet counts generally return to baseline within 2 weeks after treatment ends 7

Monitoring Requirements

• Weekly platelet count monitoring until stabilized 4
• Regular liver function tests 5
• Monitoring for signs of thromboembolic events 4

Clinical Pearls

• Treatment goal is to maintain platelet count ≥50 × 10^9/L to reduce bleeding risk, not to normalize platelet count 5
• Approximately 83% of patients may relapse after discontinuation 5
• Some patients may maintain response with reduced maintenance doses or intermittent dosing schedules 5
• In patients with chronic liver disease, eltrombopag has been associated with portal vein thrombosis when used to increase platelet counts to "healthy normal" range before invasive procedures 4

Promacta represents an important therapeutic option for patients with thrombocytopenia, particularly those who have failed conventional treatments, by addressing the underlying pathophysiology of decreased platelet production.