Brand Name: Promacta
Generic Name: Eltrombopag
Manufacturer: GlaxoSmithKline
Drug Class: Thrombopoieten Receptor Agonist
Uses:
Labeled: Indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy1. Eltrombopag is also indicated for some other cases of thrombocytopenia3.
Mechanism of Action:
Promacta is a thrombopoietin agonist. Naturally occurring thrombopoietin binds to a transmembrane receptor on megakaryocytes and platelets, which then stimulates megakaryocytopoiesis2. As a chemical agonist of this process Promacta stimulates the induction and proliferation of megakaryocytes from the bone marrow1.
Pharmacokinetics:
Tmax |
Peak concentration occurs 2 to 6 hours after oral administration. |
Vd |
Not reported.7 |
t ½ |
Approximately 21 to 32 hours in healthy subjects and 26-35 hours in ITP patients1. |
Clearance |
Not reported.7 |
Protein Binding |
In vitro studies suggest that eltrombopag is highly bound to human plasma proteins (>99%)1 |
Bioavailability |
52% following a 75 mg oral dose1 |
Metabolism:
Eltombopag undergoes oxidative metabolism by CYP1A2 and CYP2C8
Elimination:
59% of excretion occurs through the feces and 31% by urine. Approximately 20% of the drug can be found unchanged in the feces. Unchanged drug does not appear in the urine(1,3).
Efficacy:
Bussel, et al. Eltrombopag for the Treatment of Chronic Idiopathic Thrombocytopenic Purpura. N Engl J Med, 357;22. November 29, 2007.
Study Design: This study was a multicenter, randomized, double-blind, placebo-controlled trial.
Description of Study: This study followed a 1:1:1:1 ratio where they randomly assigned patients either to eltrombopag 30, 50, or 75 mg or placebo. Inclusion criteria for the study included age of at least 18 years, at least 6 month history of ITP, had received at least one previous treatment for ITP, and a platelet count of less than 30,000 per cubic millimeter. Exclusion criteria included secondary immune thrombocytopenia, hemoglobin levels of less than 10 g per deciliter, CHF, arrhythmia, thrombosis within 1 year before enrollment, or MI within 3 months before enrollment, and women who were nursing or pregnant. Participants took eltrombopag or placebo once daily for 6 weeks. The primary endpoint of the study was a platelet count of 50,000 or more per cubic millimeter. Secondary endpoints included safety and tolerability, signs of bleeding, serum thrombopoietin level, and health related quality of life. An intended sample of 272 patients (68 per group) was needed to confer a 90% power. The primary end point of a platelet count of 50,000 or more per cubic millimeter was met in a dose dependent manner among the study participants. The breakdown for the different dosages is as follows: Eltrombopag 75mg: 21/26 (81%), Eltrombopag 50mg: 19/27 (70%), Eltrombopag 30mg: 8/29 (28%), Placebo: 3/27 (11%) (p<0.001, no variance or confidence intervals reported) The results of the secondary outcome measures are as follows: Bleeding; The incidence of bleeding decreased as platelet counts increased. The incidences of bleeding events were 14% for placebo, 17% for Eltrombopag 30 mg, 7% for Eltrombopag 50mg, and 4% for Eltrombopag 75mg.
Serum Thrombopoietin Levels; There wasn’t much difference between thrombopoieten levels from baseline to the end of the study. The changes are as follows: Eltrombopag 30mg: 54 ng/L baseline; 49 ng/L at day 43, Eltrombopag 50mg: 56 ng/L baseline; 52 ng/L at day 43, Eltrombopag 75mg: 57 ng/L baseline; 45 ng/L at day 43
Quality Of Life; The only recorded difference in quality of life was a decrease from baseline in the mean emotional role score for the group taking 75 mg of Eltrombopag. (p=0.02)
Safety and Adverse Events; The most common adverse event in each group was mild to moderate headache. There was one case of cataract development but this was determined to be unrelated to the study. One death was reported from cardiopulmonary failure also unlikely to be caused by the drug.
Limitations: This study reported that many of their findings were positive and were statistically significant. The authors did not report any measures of variation or confidence intervals. I questioned how these finding might be generalized to the greater population.
Conclusion: The results of the study seemed favorable overall. The drug did not seem to have an overwhelming adverse effect profile. Certain populations such as pregnant or lactating women are cautioned in using the drug as was mentioned in the exclusion criteria. The adverse effects were similar between the groups and did not increase with increasing doses. The study showed the dose dependent efficacy of the drug. Higher doses produced greater results, which allows for more individual patient flexibility.
McHutchison, JG, et al. Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N Engl J Med, 357; 22. November 29, 2007.
Study Design: This study was an international, multicenter, double-blind, randomized, placebo-controlled, phase 2 trial.
Description of Study: In this study they hoped to show that eltrombopag would increase the platelet count in patients with cirrhosis associated hepatitis C. As a result of the increased platelet count they hoped to show that patients who were previously ineligible for antiviral medications due to low platelet counts could now maintain a 12 week antiviral regimen. This study employed a followed a 1:1:1:1 ratio where they randomly assigned patients either to eltrombopag 30, 50, or 75 mg or placebo. Inclusion criteria for this study required participants to be 18 years of age or older, have chronic HCV infection, compensated liver disease, and thrombocytopenia. Exclusion criteria consisted of participants who are pregnant, had a history of thrombosis, or were co-infected with HIV or hepatitis B. It was planned to enroll 160 patients in the study in order to achieve a power of 90%. The primary outcome of the study was the increase in the platelet count from the baseline value. The results of this treatment at the end of week 4 are as follows:
Eltrombopag 30mg: 9/12 patients reached 100,000 or more.
Eltrombopag 50mg: 15/19 patients reached 100,000 or more.
Eltrombopag 75mg: 20/21 patients reached 100,000 or more.
Placebo: 0/17 patients reached 100,000 or more.
The secondary outcome measures were reported as follows:
Safety/Tolerability
Adverse events in the initial treatment phase were similar between the groups. The most commonly reported drug related events were dry mouth, abdominal pain, and nausea. Following discontinuation of the eltrombopag treatment one patient experienced decreased visual acuity and another patient experienced petechiae. A number of patients withdrew from the study due to adverse events, which included upper abdominal pain and ascites, neutropenia, and retinal exudates.
Ability to continue to antiviral phase
Antiviral therapy was initiated in 49 patients:
Twelve weeks of antiviral therapy was completed in:
Limitations: Similar to the previous study this trial produced results that showed the efficacy of the drug eltrombopag. Once again, the measures of variance were not reported in this trial. The patient population was relatively small in these trials partly because they needed participants to be spread out across the different dose ranges. Most of the p-values were found to be statistically significant and so type 2 error wasn’t a concern.
Conclusion: The authors of this study showed once again that the drug eltrombopag has a dose dependent effect on platelet production. This study examined the safety profile of the drug and the results were similar to other published trials. Something new that this study offered was the beneficial effect of eltrombopag in allowing patients with thrombocytopenia due to viral complications to be treated with the appropriate medications.
Jenkins JM, et al. Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist. Blood. 2007;109:4739-4741.
Study Design: This study was a phase 1, placebo-controlled, single-blinded clinical trial.
Description of study: This was a phase 1 trial study. The main purpose of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of eltrombopag when administered as a once daily oral dose. The study recruited 73 healthy male subjects and randomized them into 6 groups of 12. In each group there were 9 receiving active drug and 3 receiving placebo. Each group received a different dose of the medication. Inclusion criteria for the study consisted of no previous history of DVT, thrombocytopenia, abnormal platelet function, heart attack, stroke or heart murmur. All laboratory tests should return normal results as well. Safety measurements included ECG, vital signs, serum chemistry, hematology, urinalysis, and adverse event reporting. The increase in platelet count proved to be dose dependent. The groups taking 20 mg or less had a negligible increase in platelet counts while the groups taking 30-75 mg had a more significant increase. The mean increases in platelet count for the 30-, 50-, and 75-mg dose levels were 24.1%, 42.9%, and 50.4%, respectively. Also, the increase in platelet counts did not show any signs of rebound thrombocytopenia which would cause the platelet levels to drop below baseline after discontinuation of treatment. Furthermore, platelet function remained unharmed with the newly formed platelets. Adverse events did not differ between doses of the active drug or placebo.
Limitations: This trial did have limitations as it relates to clinical practice but this is simply because it is a phase 1 trial with healthy volunteers. The focus was more on safety and other relevant data related to the drugs kinetics and mechanism rather than its usefulness in diseased patients.
Conclusion: At the beginning of the clinical life of a drug this product showed promise for further studies.
Contraindications:
There are no contraindications listed by the manufacturer.
Precautions:
Anticoagulation therapy
Asian patients
Bleeding
Bone marrow suppression
Breast-feeding
Cataracts
Children
Elderly
Hepatic Disease
Neoplastic Disease
Pregnancy
Renal impairment
Thromboembolic disease
Malignancy/tumorigenicity
Rebound thrombocytopenia
Adverse effects:
Dermatologic: Rash (≤7%), bruising (2%)
Endocrine & metabolic: Menorrhagia (4%)
Gastrointestinal: Nausea (6%), vomiting (4%), dyspepsia (2%)
Hematologic: Rebound thrombocytopenia (10%), thrombocytopenia (2%)
Hepatic: Liver function tests abnormal (10%), ALT increased (2%), AST increased (2%)
Neuromuscular & skeletal: Limb pain (≤7%), myalgia (3%), paresthesia (3%)
Ocular: Cataract (3%), conjunctival hemorrhage (2%)
Drug Interactions:
Acetaminophen: Interaction is not well known but you may see increased levels of APAP.
Aluminum Hydroxide: Any polyvalent cation may decrease the absorption of Eltrombopag.
Calcium Salts: Any polyvalent cation may decrease the absorption of Eltrombopag.
CYP2C8 Substrates: CYP2C8 Inhibitors (Atazanavirm cimetidine, lapatinib, montelukast , sorafenib, trimethoprim, zafirlukast, etc.) can increase systemic levels through metabolic inhibition. Rifampin is a CYP2C8 inducer.
Iron Salts: Any polyvalent cation may decrease the absorption of Eltrombopag.
Magnesium Salts: Any polyvalent cation may decrease the absorption of Eltrombopag.
OATP1B1/SLCO1B1 Substrates: Eltrombopag is an inhibitor of the transporter OATP1B1 and may increase the serum concentration of OATP1B1/SLCO1B1 substrates, such as atorvastatin, fluvastatin, rosuvastatin, and pravastatin. Others include methotrexate, nateglinide, and repaglinide.
Sucralfate: Any polyvalent cation may decrease the absorption of Eltrombopag.
Dosing/Administration:
Usual dose: 50 mg PO once daily on an empty stomach, patients of east-Asian ancestry should reduce the dose by 50%. Use lowest possible dose to achieve results. Max daily dose is 75 mg.
Geriatric dose: No adjustment needed. Max daily dose is 75 mg.
Pediatric dose: Safety and efficacy have not been established.
Renal impairment dose: No specific guidelines available.
Hepatic impairment dose: Use with caution. Starting dose should be 25 mg daily.3
Use in special circumstances:
Should be used with caution in patients with hepatic insufficiency. The drug is pregnancy category C. The manufacturer requires a registered program called Promacta Cares6 for use in pregnant or lactating patients.
Conclusion:
If used properly this drug appears to have some clinical utility. It has allowed patients with associated viral complications such as in hepatitis C related cirrhosis to receive antiviral treatment. It has also been shown to improve the risk of bleeding as platelet levels increase. The adverse effect profile seems fairly limited. Overall, this seems like a promising drug.
References:
Prepared by: Travis White, Doctor of Pharmacy Candidate.