Research On The Relationship Between Pharmacogenetics And Other Factors And The Immuosuppressant Concentration In Allo-HSCT Patients

Objective: Allogeneic hematopoietic stem cell transplantation requires using the immunosuppressants to prevent the occurrence of postoperative graft-versus-host disease,so as to improve the survival time.With the development of science,in addition to the basic treatment with cyclosporine A,more and more immunosuppressants are used in the second-line prevention of graft-versus-host disease.The purpose of this thesis is to analyze the gene related and non-gene related factors of immunosuppressants concentration in whole blood,in order to provide reference for the rational use of immunosuppressants after allogeneic hematopoietic stem cell transplantation.Method:1.Establish an analytical method of high-performance liquid chromatography combined with mass spectrometry to detect the whole blood concentration of sirolimus,and verify the methodology at the same time.2.Transplant patients who met the inclusion criteria from January 2021 to January 2022 were included in the research institution.The genes of donors and recipients were tested,and the basic information and drug use information of patients,relevant clinical laboratory tests and drug concentration monitoring results of immunosuppressants were collected for analysis.SPSS 26.0 statistical software was used to study the relevant factors affecting drug concentration.Result:1.The analysis method of sirolimus whole blood drug concentration meets the requirements of national standard in vivo drug analysis.Its concentration has a good Linear relationship in the range of 0.23～60 ng/ml.the typical standard curve is y=0.335x+ 0.00155（r = 0.9997）,which meets the clinical needs.2.According to the meta-analysis of 10 included studies,CYP3A5 *1 carriers need a higher dose to reach the same drug concentration range when using sirolimus.3.The concentration of sirolimus in patients with abnormal increase of aspartate aminotransferase was higher than that in normal patients.4.The corrected concentration of tacrolimus in male recipients was significantly higher than that in female recipients.5.The CC genotype of CYP3A5（rs776746）in the recipient should appropriately reduce the dosage of injectable cyclosporine on the premise of body weight administration.6.At present,there is no correlation between common drug genes of donors and cyclosporine concentration in allo-HSCT patients.Conclusion:1.In this thesis,the detection method of sirolimus whole blood drug concentration was successfully established,and the detection Limit can be as Low as0.234 ng/m L,which provides a practical method for clinical detection and further study of drug concentration in peripheral blood mononuclear cells.2.Clinically,the detection of CYP3A5（rs776746）gene can guide the rational use of sirolimus.3.For patients with abnormal Liver function,it is recommended to prevent and reduce sirolimus in advance.4.Female transplant recipients can increase the dosage of tacrolimus.5.The CC genotype of CYP3A5（rs776746）was associated with high whole blood drug concentration of allo HSCT injection cyclosporine.6.At present,there is no correlation between common drug genes of donors and cyclosporine concentration in allo HSCT patients.The individualized treatment of immunosuppressants still needs further research with a large sample size.