Study On Monitoring The Safety And Efficacy Of Irinotecan By UGT1A1 Gene Polymorphism Combined With SN-38 Therapeutic Drug Concentration

Objective:Establish an effective detection method for monitoring the concentration of 7-ethyl-10-hydroxycamptothecin（SN-38）in plasma,which is the active product of irinotecan（CPT-11）.The relationship between the blood drug concentration of SN-38,UGT1A1 gene polymorphism（*6 and*28）and the adverse reactions and efficacy induced by CPT-11chemotherapy was analyzed to optimize the individualized administration of CPT-11,so as to reduce the adverse reactions without affecting the efficacy.Methods:A total of 35 patients with malignant tumors who received irinotecan chemotherapy were collected in JinCheng general hospital affiliated to ShanXi medical university from February 2018 to December 2019.UGT1A1*6 and UGT1A1*28 gene tests were performed before chemotherapy.All patients received at least one chemotherapy cycle,and the treatment continued until the disease progressed or intolerable toxicity appeared.In addition,peripheral blood samples were collected at 2.5h and 49.5h after intravenous infusion of CPT-11,and the blood concentration of SN-38 was monitored by HPLC-FLD.All adverse reactions,such as neutropenia,leukopenia,anemia,thrombocytopenia,nausea,vomiting,diarrhea,especially neutropenia and diarrhea,were observed during chemotherapy and their clinical data were recorded in detail.The adverse reactions and efficacy were evaluated according to the toxicity and efficacy evaluation criteria.All data were statistically processed using SPSS 23.0 statistical software.Results:A total of 35 patients with CPT-11 dosage of 65-200mg/m² were included in this study,and the concentration of the active product SN-38 in their plasma was determined by HPLC-FLD.The peak concentration range of SN-38 was 5.13-191.33ng/mL,the concentration range of SN-38 valley was 0.51-15.61ng/mL,and the total AUC range of SN-38 was 204.96-3255.77ng·h·ml^-1.In addition,UGT1A1 genotype was detected in all 35 tumor patients,and the results of gene detection showed that there were 16 cases of wild type,accounting for 45.7%,there were 15 cases of unit point mutation,accounting for 42.9%and there were 4 cases of double locus mutation,accounting for 11.4%.Among them,there were 14 cases of UGT1A1*6mutation,whose gene frequencies were wild-type GG 59.4%（n=21）,mutated heterozygous type GA 35.3%（n=12）,and mutated homozygous type AA 5.3%（n=2）.There were only 6cases of UGT1A1*28 mutation,and the gene frequencies were wild-type TA6/TA6 81%（n=29）,mutated heterozygous type TA6/TA7 18%（n=5）,and mutated homozygous type TA7/TA7 1%（n=1）,respectively.It was found that the incidence of neutropenia and leucopenia of grade 3-4 and grade1-2 thrombocytopenia in UGT1A1 mutant was significantly higher than that in wild type patients（P=0.043;P=0.009;P=0.045）.After analyzed the relationship between UGT1A1*6and UGT1A1*28 gene polymorphism and adverse reactions respectively,we found that only UGT1A1*6 gene mutation was found to increase the risk of grade 3-4 neutropenia in patients（P=0.044）and no correlation between UGT1A1*28 gene polymorphism and adverse reactions was found.The study also found that the polymorphism of UGT1A1*6 and UGT1A1*28 genes was not associated with the short-term efficacy,and the difference was not statistically significant（P>0.05）.What’s more,analysis of blood drug concentration of SN-38 showed that the peak concentration of SN-38 and the total AUC value of SN-38 were significantly correlated with neutropenia for patients with UGT1A1 gene mutation（P=0.006;P=0.041）,and the peak concentration of SN-38 was also significantly correlated with vomiting（P=0.046）.But no significant correlation was found between SN-38 blood concentration and short-term efficacy,nor was it associated with UGT1A1*6 or UGT1A1*28 gene polymorphism.Conclusion:The HPLC-FLD method established in this study is sensitive,rapid,accurate and repeatable and it is suitable for the blood concentration monitoring of routine clinical practice of CPT-11 and SN-38.For malignant tumor patients treated with irinotecan clinically,if UGT1A1 gene mutation occurs,we should not only pay attention to the occurrence of neutropenia and delayed diarrhea,but also pay close attention to the occurrence of leukopenia and thrombocytopenia.In addition,the peak concentration of SN-38 and the total AUC value of SN-38 both are risk factors for severe neutropenia,and the peak concentration of SN-38 is also a risk factor for severe vomiting.Therefore,for patients with UGT1A1 gene mutation who are prone to bone marrow suppression or severe digestive tract reactions during previous chemotherapy,peak concentration detection of SN-38 can be used to optimize the personalized administration of CPT-11.