Thrombopoietin analogues (Romiplostim / Eltrombopag)

Mechanism

Mechanism of Action

Romiplostim and Eltrombopag act by mimicking the natural growth factor thrombopoietin that stimulates the marrow synthesis of megakaryocytes and the subsequent generation of platelets.

Romiplostim ("Peptibody" Recombinant)

It is an injectable chimeric recombinant fusion protein composed of a human IgG1 antibody Fc fragment fused to active peptide sequences:

• Competitively binds to the extracellular TPO-binding site of the receptor MPL receptor (TPO-R)..
• Stimulates phosphorylation of intracellular JAK2 and STAT5.
• Promotes megakaryocyte maturation and cytoplasmic fragmentation into mature platelets.

Eltrombopag (Small-Molecule Non-Peptide Agonist)

An orally bioavailable, lipophilic non-peptide hydrazone small molecule that acts through a distinct allosteric mechanism:

• Se une de forma selectiva al transmembrane domain of the TPO receptor, away from its physiological extracellular binding site.
• Initiates intracellular signaling without competing with endogenous circulating TPO.
• Synergistically promotes megakaryopoiesis.
• Requires specific metal cations to stabilize its active chelate conformation.

Pharmacokinetics

Pharmacokinetics

• Romiplostim: Administration exclusively subcutaneously once a week. Slow absorption that reaches maximum concentration in a range of 7 to 50 hours. Pharmacokinetics are non-linear and closely dependent on total peripheral platelet cell mass (target receptor-mediated cell clearance). Average elimination half-life of 1 to 3 weeks.
• Eltrombopag: Oral administration once a day. Absorption drastically decreased if administered concomitantly with polyvalent dietary cations (such as calcium, iron, magnesium, zinc or dairy) due to the formation of insoluble chelation complexes. It should be taken at least 2 hours before or 4 hours after ingesting dairy products or antacids. Extensive hepatic metabolism via CYP1A2 and CYP2C8. Plasma elimination half-life of about 21 to 35 hours.

Indicators and dose

Indications

• Treatment of thrombocytopenia in adult and pediatric patients with chronic primary immune thrombocytopenia (ITP) who have presented a refractory response to first-line treatments (corticosteroids, immunoglobulins or splenectomy).
• Treatment of thrombocytopenia in patients with chronic hepatitis C virus (HCV) infection to enable initiation and maintenance of interferon-based antiviral treatment.
• Treatment of acquired severe aplastic anemia (SAA) refractory to first-line immunosuppressive therapy (especially Eltrombopag in combination or monotherapy).

Dosage and Adjustments

• Romiplostim: Start at a weekly dose of 1 µg/kg subcutaneously. The platelet count should be measured weekly and the dosage adjusted by escalating 1 in 1 µg/kg until reaching and maintaining a safe platelet count (≥ 50,000/µL) that minimizes the risk of spontaneous bleeding without seeking to normalize the count. Maximum dose of 10 µg/kg per week.
• Eltrombopag: Recommended starting dose of 50 mg once daily orally. In patients of Asian origin (who metabolize the drug at lower rates) or with moderate hepatic impairment, the starting dose must be reduced to 25 mg once a day.

Pregnancy and Breastfeeding

FDA Category C. There is a lack of sufficient studies in pregnant women. They cross the placental barrier in animal models of toxicity. Its administration is not recommended during pregnancy or active lactation.

Security

Contraindications

Absolute

• Known hypersensitivity to the active ingredient.
• Subjects with intermediate or high risk myelodysplastic syndromes (MDS) (critical risk of accelerating tumor transformation and progression to Acute Myeloid Leukemia mediated by the stimulation of blasts that expose TPO-R).
• Severe liver failure (Child-Pugh C) without strict monitoring (especially Eltrombopag for intrinsic hepatotoxicity).

Relative

• Known underlying known thromboembolic risk factors (advanced age, prolonged immobility, genetic thrombophilia states).
• Moderate kidney failure.

Adverse effects (ADRs)

• Thromboembolic Complications: Excessive and uncontrolled increase in peripheral platelet count (> 200,000-400,000/µL) can favor phenomena of portal thrombosis, pulmonary embolism or acute myocardial infarction.
• Hepatotoxicity (Eltrombopag): Significant reversible increase in transaminases (AST/ALT) and indirect serum bilirubin. Requires laboratory monitoring of liver function tests every 2 weeks during the initiation phase of treatment.
• Medullary Reticulin (Fibrosis): Sustained and prolonged stimulation of megakaryocytes in the bone marrow can induce the release of fibroblast growth factors (such as TGF-beta), promoting cellular synthesis of reticulin and the formation of reversible bone marrow fibrosis after drug withdrawal.
• Cataracts (Eltrombopag): Reports of development or exacerbation in animal models and low frequency in human clinical trials, requiring baseline ophthalmological evaluations.

Interactions

Eltrombopag presents significant interactions by chelation with polyvalent and metabolic cations as it is a substrate and minor inhibitor of the OATP1B1 and BCRP transporters (increases serum levels of statins). Romiplostim has no known metabolic interactions of clinical clinical relevance.