European Review for Medical and Pharmacological Sciences 2012; 16: 743-746 Eltrombopag – an oral thrombopoietin agonist V. SHARMA, H. RANDHAWA, A. SHARMA, S. AGGARWAL Department of Medicine, University College of Medical Sciences, New Delhi (India) Abstract. – The therapy for immune of the thrombocytopenia. The two major throm- thrombocytopenic purpura (ITP) has evolved in bopoietin agonists which have a role in the man- the recent past. In certain cases therapy for ITP agement of the thrombocytopenia, especially the remains inadequate. Thrombopoietin receptor agonists are the latest addition to the armamen- immune thrombocytopenic purpura (ITP), in- 2 tarium to manage the thrombocytopenia. While clude romiplostim and eltrombopag . Romi- romiplostim was the first second generation plostim is a peptibody administered as once a thrombopoietin agonist to become available, el- week subcutaneous injection in non-responding trombopag is particularly attractive as it is an or relapsing ITP. Eltrombopag is a non peptide orally bioavailable agent. This review focuses on thrombopoietin agonist which has also been the use, safety and efficacy of eltrombopag in various clinical conditions. found to be efficacious in similar conditions. The fact that it is orally bioavailable makes eltrom- Key Words: bopag a more attractive option. Thrombopoietin agonists, Eltrombopag, Immune Chemistry and Structure thrombocytopenic purpura. Eltrombopag, a non-peptide synthetic throm- bopoietin receptor agonist, is a biaryl hydrazone with a molecular weight of 564.6 Dalton. Mechanism of Action Introduction Thrombopoietin, a cytokine produced in the liver, acts on the thrombopoietin receptors Thrombocytopenia (platelet count <100.000/μL) (TPO-R) which are present on the megakary- can accompany a multitude of conditions including ocytes. Thrombopoietin binds to these receptors disorders of marrow (aplastic anaemia, myelodys- and activates the Janus kinase (JAK 2) and tyro- plasias, lymphomas and leukemias), enhanced sine kinase 2 pathways. This results in the activa- immune mediated platelet destruction (Immune tion of signal transducers and activators of tran- thrombocytopenia, drug induced, secondary to scription five (STAT 5), phosphoinositide-3 ki- chronic lymphatic leukemia (CLL), etc), dissem- nase and ras-mitogen activated protein kinase inated intravascular coagulation, thrombotic (MAPK)3-5. The net result is the differentiation of thrombocytopenic purpura, septicaemia, hyper- the bone marrow precursor cells along the splenism, etc. Therapies to treat thrombocytope- megakaryocytic lineage. Thrombopoietin has an nia are still evolving and management of threat- antiapoptotic effect and stimulates megakary- ening thrombocytopenia, in resistant cases, re- ocyte maturation. Eltrombopag, in association mains inadequate. Thrombopoietin and its recep- with metal ions (Zn2+) activates the TPO-R. tors are one of the major targets of newer thera- Since the interaction between eltrombopag and pies aimed at increasing platelet counts. While endogenous thrombopoietin on the TPO-R is first generation thrombopoietin analogues in non-competitive, their effects are additive6. form of recombinant human thrombopoietin had efficacy in increasing platelet levels initially, de- Dosage and Administration velopment of alloantibodies against these ana- The FDA approved eltrombopag in November logues compromised their efficacy on a contin- 2008 for use in immune thrombocytopenic purpu- ued therapy1. ra (ITP) patients who had failed at least one prior Second generation thrombopoietin agonists therapy such as corticosteroids, immunoglobulins have emerged as a new hope in the management or splenectomy. Eltrombopag has been used in Corresponding Author: Vishal Sharma, MD; e-mail: [email protected] 743 V. Sharma, H. Randhawa, A. Sharma, S. Aggarwal dose of 25, 30, 50 and 75 mg daily for various du- Table I. Indications for use of Eltrombopag. rations in trials in patients of chronic ITP. Al- though the maximum increase in platelet levels is Approved indication seen with a dose of 75 mg, a dose of 50 mg each Immune thrombocytopenic purpura day achieves acceptable increase in platelet counts Under evaluation with a fewer side effects7. As already mentioned, Chemotherapy-induced thrombocytopenia. Hepatitis C related thrombocytopenia the drug is taken orally. If the response is inade- Thrombocytopenia due to marrow abnormalities or quate the dosage can be increased to a maximum hematologic malignancy of 75 mg. One should aim to increase the platelet Chronic liver disease related thrombocytopenia count to more than 50,000/μL, to prevent bleeding manifestations. However, normalisation of the platelets is not the goal of therapy. The drug is study reported no difference in frequency or best taken 2 hours prior to or after a meal and 6 severity of adverse effects of eltrombopag vis-a- hours after the ingestion of antacids, calcium and vis placebo. The study also demonstrated throm- vitamin supplements to achieve a predictable ab- bopoietic efficacy in normal male subjects. How- sorption and attain consistent plasma levels. A ever, lower doses (5, 10 and 20 mg) showed no randomised control trial conducted by Williams et difference in platelet counts from placebo. Bussel al[8] indicated that the concomitant administration et al[7] studied the effect of eltrombopag in adult of eltrombopag with antacids containing magne- patients with chronic ITP who had relapses or sium, aluminium or with calcium rich food re- were refractory to standard therapy. A dose de- duced its bioavailability. pendent response in form of increasing platelet counts was seen with the dose of 30, 50 and 75 Pharmacokinetics mg. In 80% of the patients the response was evi- Around 50% of the drug is absorbed after the dent within 15 days of initiation of therapy. The oral intake, and peak plasma levels are obtained safety of this drug was reconfirmed in this trial. 2-6 hours after the oral dose. Plasma elimination half-life is 21 to 32 hours. Absorption is inter- Cirrhosis due to Hepatitis C fered by concurrent aluminium and high fat Chronic hepatitis C virus infection results in au- meals, as already mentioned. The drug is highly toimmune thrombocytopenia which appears well protein bound. Eltrombopag is extensively me- before the liver failure has set in. Once cirrhosis tabolized by oxidation via that CYP 1A2 and develops, a decreased production of thrombopoi- 2C8 and is then glucuronidated. elimination oc- etin from the liver further decreases the platelet curs via both faeces and urine9. count. McHutchinson et al[10] observed a positive effect of eltrombopag on the platelet counts in pa- Indications tients with thrombocytopenia due to HCV related As of today eltrombopag is approved by US cirrhosis. The increase in platelet counts was help- FDA for use in ITP only. However, emerging ful in the completion of the antiviral therapy in a data has alluded to the role of this agent in man- significant number of patients. Dose escalation to aging thrombocytopenia associated with other 75 mg has been shown to increase the platelet etiologies. In patients with hepatitis C related counts in cases of ITP that did not respond to a cirrhosis eltrombopag has been shown to in- lower dose, i.e. 50 mg13. crease the platelet counts to above 100.000/μL, thereby, enabling the use of peg-interferon ther- Ongoing Eesearch apy. Use of eltrombopag resulted in a signifi- Trials are currently underway to explore the cant number of initially thrombocytopenic pa- role of eltrombopag in conditions like myelodys- tients achieving completion of antiviral thera- plastic syndrome, secondary acute myeloid py10. The indications for use of eltrombopag are leukemia after myelodysplastic syndrome, pa- mentioned in Table I11. tients of sarcoma receiving adriamycin and ifos- famide, aplastic anemia patients with immuno- Immune Thrombocytopenic Purpura (ITP) suppressive-therapy, refractory thrombocytope- A phase 1 placebo controlled trial to assess the nia and Wiskott-Aldrich syndrome. Trials are al- safety of various doses (5, 10, 25, 30, 50, 75 mg) so on to find if eltrombopag can reduce the need given over a period of ten days was conducted in for platelet transfusions in patients of chronic liv- healthy male subjects by Jenkins et al12. The er disease who undergo elective procedures. 744 Eltrombopag – an oral thrombopoietin agonist Table II. Important trials of Eltrombopag. References Patient subset Dosage Results Bussel et al 2007 (7) Placebo controlled 30 mg, 50 mg, Platelets > 50,000 RCT 118 chronic ITP 75 mg for 42 days was achieved in 28% Platelets <30,000/μL, (30 mg), 70% Relapsing or refractory ITP (50 mg) and 81% (75 mg) patients in three groups respectively Jenkins et al 2007 (12) 73 placebo controlled 5, 10, 25, 30, 50, No difference in adverse healthy adults 75 mg for 10 days effects between placebo and active drug Mchutchinson et al 2007 (10) Placebo controlled 30, 50, 75 mg for Platelets > i lakh/μL were RCT 74 HCV related 4 weeks achived in 75% (30 mg), cirrhotic patients with 79 (50 mg) and 95% platelets between (75 mg) 20-70.000/μL Bussel et al 2009 (13) Placebo controlled Dose of 50 mg for 59% pts on eltrombopag RCT in chronic ITP 3 wks, increased to 50 mg achieved platelet 75 mg in nonresponders count ≥50.000. Amongst nonresponders 29% dose escalation Contraindications regularly monitored. Bone marrow reticulin de- There are no known contraindications to the position is seen with the prolonged therapy. Bone use of eltrombopag.