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Immune Thrombocytopenia


Table 1: Pharmacological Characteristics of Romiplostim and Eltrombopag Romiplostim*


Chemical structure Molecular weight


Mechanism of binding to TPO-R Formulation


Route of administration


Frequency of administration C0 (pg/ml)


Cmax AUC


CL (ml/kg-1/h-1)


Peptibody 29,542Da


Similar to endogenous TPO


Powder for injection, 250 and 500µg Subcutaneous† Once weekly


2,810±1,170 at 0.3µg/kg IV


12,900±1,800 at 1.0µg/kg IV 211,000±32,000 at 10µg/kg IV –


964±1,310pg/hour/ml at 0.3µg/kg IV


26,700±19,100pg/hour/ml at 1.0µg/kg IV 1,530,000±260,000pg/hour/ml at 10µg/kg IV 754±435 at 0.3µg/kg IV


Vc (ml/kg) t½ (hour) tmax (median)


63±55.7 at 1.0µg/kg IV 6.69±1.03 at 10µg/kg IV 122±51 at 0.3µg/kg IV


78.8±10.7 at 1.0µg/kg IV 48.2±7.4 at 10µg/kg IV 1.50±2.83 at 0.3µg/kg IV


2.41±1.56 at 1.0µg/kg IV 13.8±3.9 at 10µg/kg IV 13 days at 0.3µg/kg IV


12 days at 1.0µg/kg IV 15 days at 10µg/kg IV


*In the phase I study, eligible subjects were randomised in a ratio of 2:1 to receive a single injection of romiplostin at escalating doses or placebo.33


**In the phase I study, subjects received eltrombopag or placebo as oral capsules once daily for 10 days at doses of 5, 10, 20, 30, 50 or 75mg.49 †Romiplostim was given intravenously to normal volunteers.


AUC = area under serum concentration-time curve; C0 = maximum serum concentration at time 0 after intravenous (IV) bolus administration; CL = systemic clearance; Cmax = maximum plasma concentration; NR = not reported; t½ = half-life; tmax = time when peak platelet count was observed; TPO = thrombopoietin; TPO-R = thrombopoietin receptor; Vc = central volume of distribution.


Overall, approximately 40% of patients with ITP have a reduced platelet turnover.18–20


In keeping with this finding, autoantibodies


Furthermore, most megakaryocytes found in ITP show ultrastructural features of apoptosis or para-apoptosis and these morphological changes can be induced in cultured megakaryocytes with ITP plasma.23


In vitro studies have shown that antibodies


that target the platelet glycoprotein (GP) Ib-IX-V complex may induce thrombocytopenia by inhibiting megakaryopoiesis22,24 proplatelet formation.25


A Novel Therapeutic Approach – Thrombopoietic Agents


Most traditional treatments for ITP aim to suppress the production of autoantibodies and/or inhibit macrophage-mediated destruction of opsonised platelets. However, as discussed above, several patients have impaired platelet production rather than increased platelet destruction. Additionally, ITP patients have normal or slightly elevated TPO levels, whether measured in plasma or serum. The levels are always lower than the concentrations found in thrombocytopenias resulting from megakaryocytic hypoplasia.26–28


The reasons for this


finding have not been elucidated, but probably involve active TPO uptake and destruction by the expanded megakaryocyte mass in ITP.


On these grounds, growth factor stimulation of megakaryopoiesis was expected to increase the platelet count in patients with ITP and was investigated in clinical trials. First-generation TPOs included recombinant human TPO (rhTPO) and a non-glycosylated, truncated


64 and


This lent further support to the use of second-generation thrombopoietic agents. The theoretical advantage of the second- generation TPO-R agonists, also referred to as TPO-R agonists, is that they bear no structural similarity with native TPO and should not trigger auto-immune anti-TPO antibodies as is the case with pegylated-MGDF. These novel agents include TPO peptide agonists, TPO non-peptide agonists and TPO agonist antibodies. All of these bind to and activate the TPO receptor in different ways.29 engineered to have unique pharmacological attributes.


All have been


The molecules for which clinical trials in patients with chronic ITP have been completed are romiplostim – a subcutaneously administered TPO-R peptide agonist and eltrombopag – an orally bioavailable, non-peptide TPO-R agonist (see Table 1). Clinical trials investigating another non-peptide agonist, AKR-501, in chronic ITP patients have recently been initiated.


EUROPEAN ONCOLOGY & HAEMATOLOGY


Despite this, early reports of the use of pegylated recombinant human MGDF suggested that megakaryocyte stimulation may actually be effective in ameliorating the thrombocytopenia associated with ITP.31,32


against platelet glycoproteins have been shown to interfere with the maturation of megakaryocytes, resulting in reduced platelet production.21,22


form of TPO coupled to polyethylene glycol. The recombinant protein – megakaryocyte growth and differentiation factor (MGDF) – had important differences compared with native TPO that probably explained its immunogenic potential.29


When administered


subcutaneously to platelet donors, some of the donors produced antibodies against MGDF that cross-reacted with endogenous TPO, thereby causing severe thrombocytopenia.30


This adverse event led


to the discontinuation of clinical research with both MGDF and the full-length form of TPO.


Eltrombopag**


Hydrazone organic compound 564.6Da


Different from endogenous TPO Tablets, 25 and 50mg Oral


Once daily –


7.3µg/ml at 75mg/day 79.0µg/hour/ml at 75mg/day NR NR >12 15 days at 75mg/day


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