Efficacy and safety of eltrombopag in Japanese patients with chronic liver disease and thrombocytopenia: a randomized, open-label, phase II study

Abstract

Background: Eltrombopag is an oral thrombopoietin receptor agonist that stimulates thrombopoiesis and shows higher exposure in East Asian patients than in non-Asian patients. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with thrombocytopenia associated with chronic liver disease (CLD).

Methods: Thirty-eight patients with CLD and thrombocytopenia (platelets <50,000/μL) were enrolled in this phase II, open-label, dose-ranging study that consisted of 2 parts. In the first part, 12 patients received 12.5 mg of eltrombopag once daily for 2 weeks. After the evaluation of safety, 26 patients were randomly assigned to receive either 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part.

Results: Pharmacokinetics showed that the geometric means of the maximum plasma concentration (C(max)) and the area under the curve (AUC) in the 12.5 mg group were 3,413 ng/mL and 65,236 ng h/mL, respectively. At week 2, the mean increases from baseline in platelet counts were 24,800, 54,000, and 60,000/μL in the 12.5, 25, and 37.5 mg groups, respectively. The median platelet counts increased within 2 weeks of the beginning of administration in all groups, and remained at the same level throughout the 2-week post-treatment period in the 12.5 mg group, whereas the platelet counts peaked a week after the last treatment in both the 25 and 37.5 mg groups. Most adverse events reported were grade 1 or 2; 2 patients in the 37.5 mg group had drug-related serious adverse events.

Conclusions: Eltrombopag ameliorated thrombocytopenia in Japanese patients with CLD and thrombocytopenia. The recommended dose for these patients is 25 mg daily for 2 weeks.

Figures

Fig. 1

Study design. The study was a multicenter, open-label, dose-ranging phase II study that used a unique sequential design and consisted of 2 parts. After review, by a Safety Review Committee, of safety data from the 12.5 mg group (first part), new patients were randomly assigned to receive 25 or 37.5 mg of eltrombopag once daily for 2 weeks in the second part

Fig. 2

Plasma eltrombopag concentration stratified by Child–Pugh class in the 12.5 mg (a), 25 mg (b), and 37.5 mg groups (c). One patient in the 12.5 mg group with Child–Pugh class A and another patient in the 37.5 mg group with Child–Pugh class B were excluded from summary statistics of plasma concentration, because both patients had used a cation-containing antacid, which affects the exposure of eltrombopag. Data are expressed as means ± SD

Fig. 3

Changes from baseline in platelet counts at week 2. Exploratory analyses were conducted to detect a dose response and trend, using the changes from baseline in platelet counts at week 2. These data were analyzed using analysis of covariance (ANCOVA) with baseline platelet counts as a covariate, using contrast methods for the following dose response patterns: linearity in 3 doses [contrast of 12.5, 25 and 37.5 mg: −1 0 1], saturation at the medium dose (25 mg) [contrast: −2 1 1], and onset of response at the high dose (37.5 mg) [contrast: −1 −1 2]. No adjustment for multiplicity was made. Data are expressed as means + SD

Fig. 4

Median platelet counts after treatment with eltrombopag. Platelet counts at either week 2 or 3, or at the end of treatment with eltrombopag. Platelet counts after the end of treatment include the values after invasive procedures or platelet transfusions. Data are expressed as medians with interquartile ranges (IQRs). FU follow up