Romiplostim Mechanism of Action
Romiplostim increases platelet production by binding to and activating the thrombopoietin (TPO) receptor on megakaryocyte precursors, working through a mechanism analogous to endogenous TPO but without sharing any amino acid sequence homology with it. 1
Molecular Structure and Receptor Interaction
Romiplostim is an Fc-peptide fusion protein (peptibody) consisting of two identical single-chain subunits, each containing a human immunoglobulin IgG1 Fc domain covalently linked to a peptide with two TPO receptor-binding domains 1
The drug has no structural similarity to endogenous TPO, which eliminates the theoretical risk of developing neutralizing anti-TPO antibodies that occurred with earlier recombinant TPO formulations 2, 3
Romiplostim binds to the c-Mpl receptor (TPO receptor) on megakaryocyte precursors and activates intracellular transcriptional pathways in a manner similar to naturally occurring TPO 4, 3
Pharmacodynamic Effects
Activation of the TPO receptor promotes megakaryocyte proliferation and viability, ultimately resulting in dose-dependent increases in platelet production 1, 3
Peak platelet counts occur 1.3 to 14.9 times baseline over a 2- to 3-week period following single doses of 1-10 mcg/kg in ITP patients 1
Platelet responses typically occur within 1-2 weeks of initiating treatment, with median time to response of approximately 2 weeks in clinical studies 2, 5
Clinical Relevance in ITP
The mechanism directly addresses the pathophysiology of ITP, which involves both accelerated platelet destruction and inadequate platelet production 4, 3
Unlike immunosuppressive therapies, romiplostim works by increasing platelet production rather than reducing immune-mediated destruction, making it the only widely available drug class that directly and specifically improves platelet counts through enhanced bone marrow production 2
The drug's efficacy is maintained with stable dosing for up to 5 years of continuous treatment, demonstrating sustained receptor activation without tachyphylaxis 6
Important Mechanistic Considerations
Romiplostim elimination is partly dependent on TPO receptors on circulating platelets, meaning patients with high platelet counts have lower serum concentrations and vice versa for any given dose 1
The drug crosses the placental barrier and increases fetal platelet counts at clinically equivalent and higher doses in animal studies 1
Some evidence suggests romiplostim may have disease-modifying effects beyond simple platelet production, potentially through restoration of impaired regulatory T-cell function and immune tolerance, though this remains under investigation 2