Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Marco Dionisi; Sara Cairoli; Raffaele Simeoli; Francesca De Gennaro; Valeria Paganelli; Roberto Carta; Francesca Rossi; Carlo Dionisi-Vici; Giuseppe Palumbo; Bianca Maria Goffredo

doi:10.3389/fphar.2021.772873

Pharmacokinetic Evaluation of Eltrombopag in ITP Pediatric Patients

Front Pharmacol. 2021 Dec 6:12:772873. doi: 10.3389/fphar.2021.772873. eCollection 2021.

Authors

Affiliations

¹ National Center for Drug Research and Evaluation, National Institute of Health (ISS), Rome, Italy.
² Department of Pediatric Specialties and Liver-kidney Transplantation, Division of Metabolic Biochemistry, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
³ Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
⁴ Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Scientific Institute for Research and Healthcare, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁵ Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy.

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.

Keywords: LC-MS/MS; area under the concentration–time curve (AUC); drug exposure; eltrombopag; gender and age influence; pediatric patients; pharmacokinetic (PK) evaluation; primary immune thrombocytopenia (ITP).