Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Abstract

Background: Eltrombopag (EPAG) is an oral thrombopoietin receptor agonist, approved for refractory primary immune thrombocytopenia (ITP) in pediatric patients. In two pediatric RCTs, EPAG led to an improvement of platelet counts and a reduction in bleeding severity. However, a significant number of pediatric patients did not achieve the primary endpoints. We performed a pharmacokinetic evaluation of EPAG in pediatric patients with refractory ITP.Methods: Outpatients aged from 1 to 17 y, affected by refractory ITP to first-line treatment, were enrolled for a pharmacokinetic assessment. The analysis of drug plasma concentration was performed by the LC-MS/MS platform. Non-compartmental and statistical subgroup analyses were carried out using the R package ncappc.Results: Among 36 patients eligible for PK analysis, the median dose of EPAG given once daily was 50 mg. The EPAG peak occurs between 2 and 4 h with a population Cmax and AUC 0–24 geo-mean of 23, 38 μg/ml, and 275, 4 µg*h/mL, respectively. The pharmacokinetic profile of EPAG did not show a dose proportionality. Female patients showed a statistically significant increase of dose-normalized exposure parameters, increasing by 110 and 123% for Cmax and AUC 0–24, respectively, when compared to male patients. Patients aged 1–5 y showed values increased by more than 100% considering both exposure parameters, compared to older children. Furthermore, patients presenting complete response (83%), showed augmented EPAG exposure parameters compared to subjects with partial or no response.Conclusion: These data highlight the need to further explore the variability of EPAG exposure and its pharmacokinetic/pharmacodynamic profile in pediatric patients also in a real-life setting.

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

“…Both univariate and multivariate analyses were used to analyze the correlation between response and eltrombopag concentration in ITP, but no significant difference was found. It was inconsistent with other studies, which might be because the efficacy of eltrombopag in ITP was affected by other factors 15,16 . ITP was an autoimmune‐mediated disease, and whether patients got better mainly depended on the state of their immune systems.…”

“…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. However, excessive plasma concentration or prolonged exposure to eltrombopag may result in ADRs.…”

“…ADRs were reported in many works of literature, including elevated transaminase, elevated bilirubin, headache, skin rash, nausea, fatigue, diarrhea, etc 15,16 . Pharmacokinetic studies demonstrated that the eltrombopag concentration was positively correlated with the rate of ADRs 16,18,22 .…”

“…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.…”

“…With the increasing use of eltrombopag, the importance of concentration is becoming more apparent, adverse drug reactions (ADRs), such as liver injury, skin pigmentation, and thrombocytosis may be related to higher plasma concentrations 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 …”