| Objective: To elucidate the factors influencing the clinical result of patients with acute myeloid leukemia after receiving cytarabine chemotherapy,to lay the foundation for the study of individualized drug delivery.Methods: 1)The four indicators of blood routine examination from 52 cases of newly diagnosed AML patients were selected as indexs,repeated measures analysis of varianceuse was used to investigate the influencing factors of blood routine..2)The four indicators of blood routine examination from 52 cases of newly diagnosed AML patients were selected as indexs,Spearman-correlation method,Two classification-logistic regression model,Ordered-logistic regression model were used to comprehensive investigate the relationship between basic information and risk factors of patients with various types of adverse reactions.3)A HPLC method for the determination of cytarabine and its metabolites in patients with AML was set up,methodological investigation was completed,and blood concentrations of cytosine arabinoside and uridine arabinoside under different blood sampling points in 12 patients were detected.4)The blood concentrations of cytarabine and its metabolites in 12 patients received cytarabine chemotherapy were selected as indicators,repeated measures analysis of variance,spearman-correlation method,pearson correlation analysis were used to discuss the relationship between the basic factors,blood drug concentration and adverse reactions.5)Blood concentrations of 12 patients were used to establish the population pharmacokinetic model,the model was verified,and the group and individual pharmacokinetic parameters were found through the model.Results: 1)The results of repeated measures analysis of variance showed that there was a significant difference in Hb count among patients with different disease types within 15-28 days of chemotherapy(P<0.05);there was significant differences in PLT count between the patients with different body surface area in 8-14 days of chemotherapy(P<0.05);there was a significant difference between the patients with different gender in 8-14 days of chemotherapy(P<0.05);there was a significant difference between the patients with different ages in 8-14 days of chemotherapy(P<0.05).2)The results of Spearman-correlation method,two classification-logistic regression model and ordinal-logistic regression model showed that Gender,body surface area,chemotherapy regimens were associated with bleeding and degree of bleeding in different periods after chemotherapy(P<0.05);the incidence and severity of ADR in patients with different cycles of chemotherapy were related to gender and body surface area(P<0.05);the incidence and severity of fever in different cycles of chemotherapy were related to chemotherapy regimen and body surface area(P<0.05);the incidence and severity of fatigue in different cycles of chemotherapy were related to the nationality and body surface area(P<0.05);the incidence and severity of infection in different cycles of chemotherapy were related to gender and body surface area(P<0.05);the incidence and severity of ADR in patients with different cycles of chemotherapy were related to gender,body surface area,nationality,chemotherapy regimen and disease type(P<0.05).3)Whole blood samples were treated by protein precipitation.There is a good linear relationship in the range of 1.55~198.0μg·mL-1 cytarabine concentration and peak area(r=0.9985),there is a good linear relationship in the range of 1.34~171.00μg·mL-1 uridine arabinoside concentration and peak area(r=0.9978);the lowest detectable concentration of cytarabine was 0.47μg·m L-1,and extraction recovery was 74.84%~87.74%;the lowest detectable concentration of uridine arabinoside was 0.402μg·mL-1,and extraction recovery was 77.76%~88.92%;the RSD of within-day precision of cytarabine and uridine arabinoside were less than 15%,the RSD of intra-day precision of high and middle concentration were less than 15%,he RSD of intra-day precision of low concentration was less than 20%.The concentrations of cytarabine under different time(40min,60 min,90min,120 min and 150min)were 11.63±0.43μg/μl、3.14±1.66μg/μl、3.94±1.85μg/μl、4.10±2.38μg/μl and 2.79±1.53μg/μl,the concentrations of uridine arabinoside under different time(40min,60 min,90min,120 min and 150min)were 1.69±1.02μg/μl 、 2.26±1.17μg/μl 、 2.8±1.73μg/μl 、 5.11±3.18μg/μl 、 4.22±2.04μg/μl and 2.47±0.96μg/μl 4)The results of repeated measures analysis of variance showed that there were significant differences in the concentration of 120 min and 150 min cytosine arabinoside in patients with different gender(P<0.05);there were significant differences in the concentration of 180 min uridine in patients with different gender(P<0.05);there were significant differences in the concentration of 40 min uridine in patients with different chemotherapy regimens(P<0.05);there was a significant difference in the concentration of 90 min uridine in different ethnic groups(P<0.05);there were significant differences in the concentration of 120 min uridine in patients with different body surface area(P<0.05).There were a relationship between patient genders,concentrations of 90 min,150min,150 min cytosine arabinoside,concentrations of 60 min and 150 min uridine arabinoside and the degree of blood system ADR in patients after accept chemotherapy.5)Cytarabine population pharmacokinetic model was set up,and through the verification,the model fitting the pharmacokinetic parameters of 12 patients group typical values are: θ3 = 3.47 L/h,θ4 = 21.1 L,θ5 = 29 L/h and θ6 = 129 L.In fitting degree variation between individuals,fixed three variables,the pharmacokinetic parameters Q variability between individual ?5 = 0.915.Cytarabine type blood drug concentration ratio error of the model ?1 = 8.39.Conclusion: 1)The basic information of the patients were correlated with the clinical results.The correlation between various adverse reactions and information in the specific time of chemotherapy was determined,which could provide sufficient conditions for the subsequent individualized administration.2)A high performance liquid chromatography method was established for the simultaneous determination of cytarabine and its metabolites concentration in patients with acute myeloid leukemia(AML).3)The clinical outcome of patients receiving chemotherapy was related to the concentration of cytarabine and uridine arabinoside,the blood concentrations of cytosine arabinoside and uridine were affected by the chemotherapy regimen,gender and other factors.The blood count for evaluating the curative effect was affected by the concentrations of cytosine arabinoside and uridine.Therefore,it is reasonable and feasible to predict the adverse events of cytarabine and monitor the prognosis of cytarabine.4)The population pharmacokinetic model about cytarabine blood concentrations of through the model validation is proved to be reasonable,feasible,and lay a foundation for cytarabine individualized medication. |
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