Correlation of the Plasma Concentration of Eltrombopag With Efficacy in the Treatment of Refractory Aplastic Anemia: A Single-Centre Study in China

Abstract

Background and purpose: Eltrombopag (ELT) can be effective in the treatment of relapse/refractory aplastic anemia (AA) patients. Responses and adverse drug reactions (ADRs) differed greatly among individuals treated at the same dosage of ELT.Methods: Patients diagnosed with nonsevere aplastic anemia (NSAA) between January 2018 and January 2019 in Peking Union Medical Colleague Hospital who were refractory to immunosuppressive therapy were treated with ELT and followed up for at least 6 months. Plasma concentrations of ELT were detected by high-performance liquid chromatography-mass spectrometry after at least two months of ELT treatment and treatment at the same dosage for at least 2 weeks. The dose-concentration, concentration-response and concentration-ADR relationships were evaluated.Results: Among the 72 patients treated with ELT during the study period, 44 patients with complete data were enrolled. Six (13.6%) were males, and 38 were females (86.4%), with a median age of 54 years [interquartile range (IQR): 38.5–63]. At the time the ELT plasma concentration was detected, the median dosage of ELT was 75 (IQR 50–100) mg/d, the median time of total ELT exposure was 3 (IQR 2.0–6.0) months, and 37 (70.5%) patients had responded to ELT. The median concentration of ELT was 10.4 μg/ml (IQR 3.7–24.4 μg/ml). The concentration of ELT was positively correlated with the daily dose of ELT (r = 0.68, p < 0.001). Multivariate logistic regression analysis showed that the risk of inefficacy of ELT at a concentration between 11.2 and 15.2 μg/ml was 0.028-fold (95% CI: 0.001–0.864; p = 0.041) of that at a concentration between 3.2 and 7.2 μg/ml. The cutoff value for the concentration of ELT showing efficacy was 12.50 μg/ml according to the receiver operation characteristic curve. A higher risk of ADR was related to a longer total exposure to ELT (p = 0.012). Although the correlation was not significant, the odds ratio increased with the ELT concentration, suggesting that it was possible that an elevated risk of ADR was correlated with the ELT blood concentration.Conclusion: ELT is effective for the treatment of NSAA and has acceptable side effects. The plasma concentration of ELT was correlated with the dose and the effects of ELT.

Spotlight on eltrombopag concentration in pediatric immune thrombocytopenia: A single‐center observational study in China

“…Some studies indicate that insufficient concentration may impact the efficacy of eltrombopag. Zuo et al 15 discovered that the risk of eltrombopag inefficacy in aplastic anemia at a concentration between 11.2 and 15.2 µg/ml was 0.028-fold (P = 0.041) of that at a concentration between 3.2 and 7.2 µg/ml in a prospective and longitudinal cohort study. Dionisi et al 16 found that patients presenting a complete response showed augmented eltrombopag exposure parameters compared to subjects with partial or no response in ITP.…”

“…13 Another case was reported of a 57-year-old female from China with chronic ITP who developed reversible hyperpigmentation after several months of treatment with eltrombopag . 14 In addition, Zuo et al 15 found that an elevated risk of ADRs might be correlated with eltrombopag concentration. Furthermore, the plasma concentration of eltrombopag, which may be affected by gender, age, race, concomitant drugs, and other factors, has a great individual variation.…”

“…13,14 On the contrary, the lack of an increase in platelet count may be attributed to lower plasma concentration. 15,16 Although a practical cutoff value for concentration 2 h after eltrombopag administration in aplastic anemia has been reported, the appropriate concentration for ITP remains unclear. 15 Especially, noteworthy is observed variability in the clinical responses and ADRs among individuals, even when administered the same dosage.…”

“…15,16 Although a practical cutoff value for concentration 2 h after eltrombopag administration in aplastic anemia has been reported, the appropriate concentration for ITP remains unclear. 15 Especially, noteworthy is observed variability in the clinical responses and ADRs among individuals, even when administered the same dosage. 17,18 Currently, there is limited research on the clinical significance of eltrombopag concentration in patients with ITP in daily clinical practice.…”

Eltrombopag-induced liver dysfunction during the treatment of immune thrombocytopenia and its risk factors

“…Acute liver failure induced by eltrombopag may be caused by an impaired elimination of the drug due to genetic variants involved in the major pharmacokinetic pathways, leading to the high plasma eltrombopag accumulation in the body. Further research is needed to investigate the proper dose of eltrombopag in Chinese populations and different age groups and the relationships between the plasma concentration or pharmacogenetic of eltrombopag and its safety and efficacy (16).…”