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

Abstract

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. 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. 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 (> 11.2μg/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. 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.