A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia

Abstract

Summary. Background: Eltrombopag is an oral, non‐peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non‐East Asian ITP descent. Objectives: To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. Patients: We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30 000 μL−1 in a multicenter study comprising a randomized, double‐blind, placebo‐controlled phase for 6‐week evaluation (15 eltrombopag, and eight placebo) and an open‐label phase for 6‐month evaluation (23 eltrombopag). Results and Conclusions: The response rate (platelet count of ≥ 50 000 μL−1) at week 6 of the 6‐week double‐blind phase was 60% in eltrombopag‐treated patients and 0% in placebo‐treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6‐month open‐label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5–50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).

Multicentre, randomised phaseIIIstudy of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia

“…The PK and PK/PD of eltrombopag in Chinese patients were well characterized, and were in agreement with findings from previous PK studies in Asian populations Hayes et al, 2011;Tomiyama et al, 2012). The estimated AUC 0-s at steady state after eltrombopag 50 mg once daily in Chinese patients from the current study (135 lg.h/ml) was similar to the previously estimated AUC 0-s in East Asian patients (163 lg.h/ml), and was 55% higher than the estimated AUC 0-s in the other populations (87 lg.h/ml) .…”

“…The primary endpoint [i.e., the odds of achieving a platelet count ≥50 9 10 9 /l at the Day 42 (Week 6) visit] was 26Á08 times greater in the eltrombopag group than the placebo group (P < 0Á001). The proportion of patients who achieved platelet counts ≥50 9 10 9 /l with eltrombopag (57Á7%) was similar to those reported in previous studies: 59% in an international phase III study of 50 mg eltrombopag (Bussel et al, 2009) and 60% in a Japanese study (Tomiyama et al, 2012). In contrast to placebo, eltrombopag treatment raised platelet counts rapidly (within 1-2 weeks, with the full treatment effect seen by Week 4), and maintained platelet counts of ≥50 9 10 9 /l at ≥75% of assessment in 22Á1% of patients versus 2% of placebo patients from weeks 1 to 6.…”

“…If these agents are unsuccessful, splenectomy, rituximab to target B cells (although this is contraindicated in patients with hepatitis B), more potent immunosuppression or thrombopoietin receptor agonists (eltrombopag or romiplostim) should be considered to stimulate platelet production. Eltrombopag has shown efficacy in raising platelet counts and reducing bleeding in short-and longer-term studies in mostly Western (Bussel et al, 2007(Bussel et al, , 2009Saleh et al, 2013) or Japanese (Tomiyama et al, 2012;Katsutani et al, 2013) patients with ITP. Asian ITP patients have been included in two previous studies of eltrombopag: the 6-month phase III randomised placebo-controlled ITP RAISE study with eltrombopag (Cheng et al, 2011) and the long-term eltrombopag extended dosing (EXTEND) study, the interim analysis of which included patients that received eltrombopag treatment for up to 3 years (Saleh et al, 2013).…”

Is There a Role for Low-Dose Eltrombopag as Maintenance Therapy in the Treatment of Immune Thrombocytopenia?

“…Although generally well tolerated [11,12,18,26,27], early adverse effects of eltrombopag include headache, fatigue, nausea, nasopharyngitis [6,18] as well as hepatic dysfunction [8,11,26]. Moreover, eltrombopag treatment has been associated with thromboembolic events [11,18,26] although further research is required to ascertain a direct relationship between these events and the use of thrombopoietin receptor agonists [19,20,21,22]. Bone marrow fibrosis is the main later adverse effect, and its incidence, clinical importance and long-term consequences need to be further investigated [13,18,28,29,30].…”

Risk of Thromboembolism in Patients with Immune Thrombocytopenia

“…Arterial and/or venous TEEs occurred in these patients. In 8 randomized controlled trials, TEEs occurred in 0% to 6.7% of eltrombopag-or romiplostim-treated patients and 0% to 25% of patients in the placebo/standard of care group [51][52][53][54]57,58,[60][61][62]. [64].…”