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Relationship between CYP2C8, UGT1A1, and ABCG2 gene polymorphisms and the exposure, efficacy, and toxicity of eltrombopag in the treatment of refractory aplastic anemia

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Abstract

Purpose

Eltrombopag (ELT) is an effective drug for relapsed/refractory aplastic anemia (AA). Our previous study showed that ELT concentration was correlated with the effects of ELT. However, the factors affecting ELT concentration in patients with relapsed/refractory AA were not clarified. Therefore, we aimed to evaluate correlations between drug disposition–related gene polymorphisms and the concentration, efficacy, and toxicity of ELT.

Methods

Forty-five patients who underwent ELT administration from January 2018 to January 2019 at Peking Union Medical Colleague Hospital (PUMCH) were included. The corresponding clinical information was also collected. ELT plasma concentrations were detected by high-performance liquid chromatography-mass spectrometry (HPLC/MS). CYP2C8, (UGT)1A1, and ABCG21 were genotyped by polymerase chain reaction (PCR). The influence of gene polymorphisms on the plasma concentration, efficacy, and toxicity of ELT was analyzed.

Results

The mean dose required to obtain the optimal effects was significantly lower in the UGT1A1*6 variant carriers than in the UGT1A1*6 WT carriers. There was a significant correlation between the (UGT)1A1*6 polymorphism and higher ELT plasma concentrations (> 11.2 μg/mL). By logistic regression analysis, the efficacy of ELT was related to plasma concentration and a combined genotype of (UGT)1A1*6 and ABCG2. There were no significant associations between genotypes and adverse drug reactions (ADRs) or ELT concentrations and ADRs.

Conclusion

UGT1A1*6 is a predictor of the ELT plasma concentration and may help to determine the initial therapeutic dose in relapsed/refractory AA patients. Both drug exposure and patient genotype should be considered for better responses to ELT.

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Data availability

Data are available on request from the corresponding author.

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Funding

This study was supported by the Chinese Academy of Medical Sciences (CAMS) innovation fund for medical sciences (CIFMS 2021-I2M-1–003); the National Natural Science Foundation of China Grants (81974183, 81970106, 81601033); and the Fundamental Research Funds for the Central Universities (2020-RW310-003).

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Authors and Affiliations

  1. Department of Pharmacy, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical Colleague Hospital, Chinese Academe of Medical Science, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China

    Wei Zuo & Bo Zhang

  2. Department of Pharmacy, Beijing Xiaotangshan Hospital, Beijing, 102211, China

    Bo Liu

  3. Department of Hematology, Peking Union Medical Colleague Hospital, Chinese Academe of Medical Science, No. 1 Shuaifuyuan, Wangfujing, Dongcheng District, Beijing, 100730, China

    Miao Chen & Bing Han

Authors
  1. Wei Zuo
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  2. Bo Liu
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  3. Miao Chen
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  4. Bo Zhang
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  5. Bing Han
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Contributions

Wei Zuo performed the research and wrote the manuscript; Bo Zhang and Bing Han designed the research; Bo Liu and Miao Chen analyzed the data. All authors reviewed the manuscript.

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Correspondence to Bo Zhang or Bing Han.

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This research was reviewed and approved by the Ethical Committee of the Peking Union Medical College and Chinese Academy of Medical Sciences (Beijing, China). All the research was conducted in accordance with the Declaration of Helsinki.

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Zuo, W., Liu, B., Chen, M. et al. Relationship between CYP2C8, UGT1A1, and ABCG2 gene polymorphisms and the exposure, efficacy, and toxicity of eltrombopag in the treatment of refractory aplastic anemia. Eur J Clin Pharmacol 78, 1657–1666 (2022). https://doi.org/10.1007/s00228-022-03367-2

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