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1345 Efficacy, Safety, and Population Pharmacokinetics of Eltrombopag in Children with Different Severities of Aplastic AnemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Acquired: Poster I
Hematology Disease Topics & Pathways:
Research, Bone Marrow Failure Syndromes, Clinical Research, Aplastic Anemia, drug development, pediatric, Diseases, real-world evidence, Therapies, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Wei Zhang1*, Li-xian Chang2,3*, Bei-bei Zhao2,3*, Dan-dan Shan1*, Bo-hao Tang1*, Fan Yang1*, Yue Zhou1*, Guo-xiang Hao1*, Yi Zheng1*, Ya-hui Zhang1,4*, John Van Den Anker5,6,7*, Xiaofan Zhu, MD2,3*, Li Zhang2,3* and Wei Zhao1,8*

1Department of Clinical Pharmacy, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical Colleg, Tianjin, China
3Tianjin Institutes of Health Science, Tianjin, China
4Department of Pharmacy，Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
5Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, the George Washington University School of Medicine and Health Sciences, Washington, DC
6Division of Clinical Pharmacology, Children’s National Hospital, Washington, DC
7Department of Pediatric Pharmacology and Pharmacometrics, University of Basel Children’s Hospital, Basel, Switzerland
8NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, Qilu Hospital of Shandong University, Shandong University, Jinan, China

OBJECTIVES: Eltrombopag (EPAG) was initially approved by the U.S. Food and Drug Administration (FDA) as first-line treatment, combined with standard immunosuppressive therapy, for patients older than two years old with severe aplastic anemia (SAA). However, the use of EPAG in children with different types of aplastic anemia (AA), especially non-severe AA (NSAA) has been limited. Therefore, we decided to investigate the efficacy, safety, and pharmacokinetics of EPAG in children with NSAA, SAA, and very severe AA (VSAA).

METHODS: A prospective, open-label, observational study was conducted at the Institute of Hematology and Blood Diseases Hospital, Tianjin, China. The efficacy including complete response (CR), partial response (PR), and no response (NR), as well as safety was assessed every three months after the start of treatment. A non-linear mixed-effects population pharmacokinetic (PPK) model was used to depict the pharmacokinetic profile of EPAG. We explored the exposure-response relationship of EPAG in patients with different types of AA. This study was registered at ClinicalTrials.gov (NCT03844360).

RESULTS: A total of 23 AA children with an average age of 7.9 (range of 3.0 - 14.0) years were enrolled in this study for efficacy, safety, and PPK analysis. Fifteen patients had a treatment response (5 had CR and 10 had PR). The response rate was 12.5% after 3 months, 50.0% after 6 months, and 100% after 12 months of treatment for patients with NSAA. For patients with SAA and VSAA, these response rates were 46.7%, 61.5%, and 87.5%. Hepatotoxicity occurred in one patient. Fifty-three blood samples were collected and analyzed to build the PPK model using allometric scaling with fixed exponents. Body weight significantly affected EPAG's apparent clearance and volume of distribution. The mean (range) of the area under the concentration-time curve from time zero to infinity (AUC∞) was 316 (131 - 809) μg×h /mL. Twenty patients with genotypes were included in the genotype analysis. The apparent clearance of EPAG was significantly higher in allele-T carriers of adenosine triphosphate-binding cassette G2 (ABCG2) (rs2231142, G>T) (p=0.02). In patients with clinical response, children with NSAA exhibited lower AUC∞, higher apparent clearance, and higher weight-adjusted apparent clearance than those with SAA or VSAA, although the differences were not significant.

CONCLUSIONS: This study enriched the efficacy and safety of EPAG in children with different types of AA. Body weight and ABCG2 genotype significantly influence EPAG clearance. The results may support further individualized treatment of EPAG in children with AA.

Disclosures: No relevant conflicts of interest to declare.

OffLabel Disclosure: The use of eltrombopag (EPAG) treating children with acquired aplastic anemia in China is off-label but in-label in the US and EU. This study aimed to investigate the efficacy and safety of EPAG in children with different types of aplastic anemia and establish a population pharmacokinetic model to describe the pharmacokinetic behavior of EPAG, and to locate the physiological and genetic factors that might result in the variability of its exposure.

See more of: 508. Bone Marrow Failure: Acquired: Poster I
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