Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food-drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single-dose, 2-period crossover design was employed, involving fasting and fed conditions with a 10-day washout period. Ninety-six healthy volunteers received a single oral dose of 25 mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high-fat, low-calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration-time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%-125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high-fat, low-calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations.

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We performed a double-blind, double-dummy controlled study to compare the efficacy between recombinant human thrombopoietin (rhTPO) and eltrombopag in rapidly increasing the platelet counts in Chinese patients with immune thrombocytopenia (ITP). A total of 96 patients diagnosed with ITP for ≥6 months who had baseline platelet counts of <30 × 109 /l were randomly assigned (1:1 ratio) to receive eltrombopag 25 mg/day or rhTPO 300 u/kg for 2 weeks. Compared with the eltrombopag group, a significantly higher proportion of patients in the rhTPO group achieved platelet counts of ≥50 × 109 /l [75·00% (36/48) vs. 43·75% (21/48), P = 0·003] or complete response (64·58% vs. 25·00%) on day 15. Moreover, a higher proportion of patients in the rhTPO group either had platelet counts that rapidly increased to twice that of baseline and with platelet counts of ≥30 × 109 /l, or reached ≥50 × 109 /l at least once when analysed on day 9, 12, and 15. However, upon discontinuation of the treatment, the platelet counts reduced to the baseline within 1 week in the rhTPO group, but on the fourth week in the eltrombopag group. Adverse events were similar in patients given rhTPO and eltrombopag. To conclude, rhTPO is superior to eltrombopag at 25 mg/day in rapidly increasing platelet counts in patients with ITP (ClinicalTrials.gov Identifier: NCT03771378).

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OBJECTIVES:

</b>Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, has been shown to increase platelet counts in adults with chronic immune thrombocytopenia and chronic hepatitis C. This multicenter phase 2 study assessed the efficacy and safety of eltrombopag in patients receiving first-line carboplatin/paclitaxel for the treatment of advanced solid tumors.<b>

RESEARCH DESIGN AND METHODS:

</b>Patients (N = 183) were randomized to placebo or eltrombopag 50 mg, 75 mg, or 100 mg given orally following chemotherapy on days 2 through 11 of each 21-day cycle, for at least two cycles. The primary endpoint was the difference in platelet count from day 1 in cycle 2 to the platelet nadir in cycle 2.<b>Clinical Trial Registry Number: </b>NCT00102726.<b>

RESULTS:

</b>Although the primary endpoint was not met, postnadir platelet counts increased during cycles 1 and 2 in all eltrombopag treatment groups compared with placebo. The most commonly reported adverse events across all study arms (including placebo) were nausea and alopecia and eltrombopag was generally well tolerated.<b>

CONCLUSIONS:

</b>This study provides preliminary information that eltrombopag does increase platelets in patients receiving chemotherapy for advanced solid tumors. Further investigation is needed to identify the optimal dose(s) and schedule of eltrombopag in patients receiving myelosuppressive chemotherapy.

Patients with persistent/chronic immune thrombocytopenia (cITP) have low platelet counts, increased risk of bleeding and bruising, and often suffer from reduced health-related quality of life (HRQoL). cITP treatments may either improve HRQoL by increasing platelet counts or decrease it because of side effects. The open-label EXTEND study (June 2006 to July 2015) evaluated long-term safety, tolerability, and efficacy of eltrombopag (an oral thrombopoietin-receptor-agonist) in adults with cITP who completed a previous eltrombopag ITP trial. The final results of EXTEND were published and used to assess changes in patient-reported HRQoL over time and association between HRQoL and platelet response. Four validated HRQoL instruments were administered: SF-36v2 including physical component summary (PCS) and Mental Component Summary; Motivation and Energy Inventory Short Form (MEI-SF); Fatigue Subscale of FACIT (FACIT-Fatigue); and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6). For the 302 patients enrolled, median duration of eltrombopag treatment was 2.37 years. All 4 HRQoL instruments demonstrated positive mean changes from baseline over time adjusted for patient baseline characteristics and rescue therapy use, and had positive association with platelet response (platelet count ≥30 × 10[9] /L; ≥50 × 10[9] /L; and ≥50 × 10[9] /L and >2 times baseline). Improvements from baseline started within 3 months and persisted through 5 years of treatment for FACIT-Fatigue and FACT-Th6 (P <.05 for nearly all time points); through 2.5 years for SF-36v2 PCS and less consistently for the MEI-SF. In conclusion, in addition to eltrombopag increasing platelet counts and reducing bleeding/bruising, it also alleviated fatigue, concerns about bleeding and bruising, and improved physical function in many patients, especially responders.

Background: EXTEND (June 2006 to July 2015) was an open-label, dose-adjustment extension study to evaluate the safety and efficacy of eltrombopag for the treatment of patients with chronic immune thrombocytopenia (cITP) who had previously been enrolled in an eltrombopag trial. CITP may lead to fatigue and interference with daily activities, and ultimately affect health-related quality of life (HRQoL). Objective: To assess patient-reported HRQoL changes over time during long-term treatment with eltrombopag in patients with cITP using the final EXTEND data. Methods: Four standard validated HRQoL instruments for chronic disease were used in this study: SF-36v2 including the Physical Component Summary (PCS) and Mental Component Summary (MCS) to measure general physical and mental health status; Motivation and Energy Inventory Short Form (MEI-SF) to measure motivation and energy; Fatigue Subscale of FACIT (FACIT-F) to measure symptoms of fatigue; and FACT-Thrombocytopenia Subscale Six-Item Extract (FACT-Th6) to measure concerns related to bleeding and bruising and their impact on usual activities. The instruments were used at baseline (BL) and at a frequency of every 3 months until last on-treatment assessment. Patients were blinded to their current platelet count results before completing the questionnaires. Generalized estimating equations were used to estimate mean changes in HRQoL from BL to different time periods for each instrument, accounting for within-patient correlation. The models adjusted for time period from BL, demographic characteristics, BL clinical characteristics (BMI, BL use of cITP medication, prior splenectomy, prior eltrombopag use, and BL platelet count), and time-varying covariates for rescue therapy use (defined as the composite of new cITP medication, increased dose of cITP medication from BL, platelet transfusion, and splenectomy). Adjusted mean best changes in HRQoL from BL were also estimated using a similar method. Proportions of responders based on minimally important difference (MID) from BL were identified for each of the instruments. Response was defined as a change from BL score of at least one-half the standard deviation (SD) of the normalized scores (5 points) for SF-36v2 PCS and SF-36v2 MCS, at least one-half the SD of BL scores observed across all patients for MEI-SF and FACT-Th6, and at least 3 or 5 points for FACIT-F. Proportions of patients achieving any improvement and time to best improvement from BL were also reported. Results: 302 patients were enrolled in EXTEND. By instrument, 289 to 293 patients had a BL and at least one on-treatment HRQoL assessment for analysis. Median treatment duration was 2.4 years. All HRQoL instruments had positive mean changes from BL over time; noticeably improvements from BL persisted through 5 years of treatment for FACIT-F and FACT-Th6 (nearly all p<0.05) (Table 1) and through the median duration of eltrombopag treatment for SF-36v2 PCS. All HRQoL instruments had a statistically positive and clinically meaningful (greater than MID threshold) mean best change from BL (p<0.01) (Table 2). About half of patients had a response at least once during treatment based on MIDs in changes from BL.: 45.4% (SF-36v2 PCS); 44.7% (SF-36v2 MCS); 42.3% (MEI-SF); 57.5% (3 points) and 47.3% (5 points) for FACIT-F; and 49.5% (FACT-Th6). Most patients experienced an improvement from BL (a higher post-baseline score at least once): 84.9% (SF-36v2 PCS); 82.8% (SF-36v2 MCS); 79.9% (MEI-SF); 77.1% (FACIT-F); and 80.6% (FACT-Th6). Best improvement occurred at a median of 6-10 months post BL. Conclusion: About 80% of patients with cITP treated with eltrombopag experienced an improvement from BL in HRQoL, often within a year of BL. About half of patients achieved a clinically meaningful response from BL. This study found positive and meaningful mean best changes from BL in all HRQoL scores, including those measurements more closely related to clinical outcomes such as fatigue, bleeding, and bruising as well as more general measures such as motivation, energy, physical and mental health status. Improvements from BL persisted over time in particular for fatigue, bleeding, bruising, and physical health status. (Figure Presented).

• Bioequivalence of eltrombopag film-coated tablets • Safety evaluation of eltrombopag film-coated tablets

A 65-year-old man with nonsevere aplastic anemia received rabbit anti-thymocyte globulin and cyclosporine and partially responded. Six months after the initiation of treatment, he was diagnosed with stage IV angioimmunoblastic T-cell lymphoma and received chemotherapy. PET/CT scan analysis indicated a complete response. However, he showed sustained myelosuppression and was diagnosed with relapse of aplastic anemia. He did not respond to cyclosporine, eltrombopag or methenolone. Fifteen months after eltrombopag administration, he developed MDS with t(3;21)(q26.2;q22). Patients should be monitored carefully for the emergence of not only -7/del(7q) but also 3q26 abnormalities, including t(3;21)(q26.2;q22), during and after eltrombopag treatment.

Background: Severe Aplastic Anemia (SAA) is a rare bone marrow disorder characterized by inadequate levels of peripheral, multi-lineage blood cells. Of the two available first-line treatments for SAA, allogeneic hematopoietic stem cell transplantation is limited by patient eligibility and donor availability, and immunosuppressive therapy (IST) is characterized by a significant proportion of non-responders, toxicity, and risk of transformation to diseases such as acute myelogenous leukemia. Patients who do not respond to treatments become transfusion dependent, which has a significant impact on patients' quality of life as well as healthcare costs. Eltrombopag is the only TPO-R agonist approved for the treatment of refractory SAA. In a Phase I/II clinical trial, eltrombopag, given in association with IST, showed efficacy in patients with naive-SAA, and offers a significantly improved first-line alternative to patients affected by SAA (Townsley, et al 201 7). In the US healthcare environment, there is a need to compare costs and consequences to understand value. Objective: Evaluate eltrombopag as a first-line treatment versus IST alone for SAA from the American private healthcare system perspective. Methods: A responder model for newly diagnosed SAA patients was created to assess the treatment pathway and economic impact of including eltrombopag in addition to IST (antithymocyte globulin and cyclosporine A) as a first-line treatment. A simulated cohort with two treatment arms underwent 6 months of treatment with either eltrombopag in addition to IST or with IST alone and were followed for a 3-year time period. Each arm received a diagnostic test measuring response at 6 months. Patients who achieved complete or partial response in either arm received low-dose cyclosporine A as maintenance therapy for an additional 6 months of treatment. Patients who did not respond in either arm continued with eltrombopag monotherapy as a second-line therapy for an additional 6 months. First-line therapy (eltrombopag with IST, IST alone), maintenance therapy (low-dose cyclosporine A), second-line therapy (eltrombopag monotherapy), administration, routine care, mortality and adverse event costs were included in the analysis. Workplace productivity related costsHelp were not considered. Response rates, mortality, dosing, treatment duration and adverse event rates for each arm were based on a phase I/II trial (Townsley, et al 201 7). Drug costs were obtained from a large online database (REDBOOK Online). Administration costs were based on the 201 7 CMS Medical Fee Schedule. Routine care rates (visits, hospitalizations, tests and transfusions) were based on published data (Peffault De Latour, et al, 201 7). Routine care, mortality and adverse event costs were based on CPT codes from the American Medical Association, HCUPnet and published data (Toner, et al 2011). All cost data are reported in 201 8 US dollars. See figure 1 for details. Results: In a simulated cohort with a population of one million, the annual incidence of aplastic anemia was 0.000234% and SAA accounted for 83.8% of those cases. The two treatment paths were compared for their consequences. Based on the clinical trial data, in the treatment arm with eltrombopag and IST, 94% of patients experienced treatment response relative to the IST arm where only 66% of patients experienced treatment response. Further, in the treatment arm with eltrombopag and IST, the patients experienced a reduced annual risk of mortality by 0.3% relative to the IST arm. Use of eltrombopag therapy as a first-line therapy produced a cost increase of $77,442 over 3 years. First-line drug costs accounted for an increase of $1 09,1 47, while improvements in response rates led to cost offsets for second-line drugs and produced $29,663 in savings. Ad event, routine care and mortality costs had relatively negligible effects on either treatment arm over a 3-year time period. Sensitivity analys confirmed the robustness of the analysis. Conclusion: When following treatment approaches specified in clinical studies, high response rates combined with reduced risk of mortality and less usage of rescue medication, and a low disease incidence are likely to lead to manageable economic consequences with eltrombopag + IST therapy from the American private healthcare system perspective. In a simulated cohort with a population of one million, this was estimated to be $77,442 over 3 years.