Study On Population Pharmacokinetic Model Of Docetaxel Given To Breast Cancer Patients Based On Drug Gene Polymorphism

Breast cancer is one of the most common malignant tumors in the world that threatens women life and health,and it tends to be younger.Docetaxel is widely used as a key drug in clinical chemotherapy for breast cancer patients.Docetaxel is a semi-synthetic taxane that has significant clinical efficacy and is often used alone or in combination with other chemotherapeutics for a variety of malignancies.However,docetaxel has significant pharmacokinetic and pharmacodynamic differences,which are not effective in the chemotherapy of breast cancer,leading to adverse reactions.Related studies have shown that drug gene polymorphisms are important genetic factors that affect pharmacokinetics and pharmacodynamics of drugs.So far,no research has been conducted on the effect of genetic polymorphisms on the population pharmacokinetics of docetaxel in the treatment of Chinese breast cancer patients.Therefore,this study will explore the effects of drug metabolism transport genes(ABCB1 3435T> C,ABCB1 2677T> G,CYP1B1 * 3 4326C> G and CYP3A5 * 36986A> G)and non-genetic factors(age,weight,body surface area,liver and kidney function,and combined medication)on the population pharmacokinetics of the docetaxel.A population pharmacokinetic model of the docetaxel was constructed to provide scientific guidance for the individualized administration of Chinese breast cancer patients.Objective:1.Establish a population pharmacokinetic model suitable for domestic individualized use of docetaxel in breast cancer patients.2.To explore the influence of genetic factors and non-genetic factors on the pharmacokinetic characteristics of docetaxel in the treatment of breast cancer patients,and to provide scientific guidance for individualized medication of clinical breast cancer patients.Methods:1.Establish a latex immunoturbidimetric method for the determination of docetaxelblood drug concentration,and obtain blood drug concentration data for breast cancer patients.2.Using digital fluorescent molecular hybridization to detect genotypes,calculate the genotype frequency,and understand the distribution characteristics of gene polymorphisms.3.Collecting breast cancer patients who received chemotherapy in October2018-November 2019 in the clinical oncology department of the First Affiliated Hospital of Bengbu Medical College,and used NONMEM software to establish the population pharmacokinetic model.The non-hereditary and genetic factors of patients were included as covariates in the construction of the model.The plasma concentration of docetaxel was fitted and the parameters were estimated to establish the final population pharmacokinetic(PPK)model.4.The final PPK model was verified by using goodness-of-fit graphs,bootstrap,and simulation-based visual predictive checks(VPC)to examine the stability and predictive ability of the model.Results:1.The blood concentration data of 121 docetaxel in 53 breast cancer patients were used to establish the population pharmacokinetic model。2.The genotypes were detected in 50 patients.The frequency of CYP3A5 * 3 6986A>G genotype distribution was GG 27(54%),AG 19(38%),and AA 4(8%),respectively.The frequency of CYP1B1 * 3 4326C> G genotype distribution was CC 35(76%),GC14(28%),and GG 1(2%).ABCB1 3435T> C genotype distribution frequency was CT27(54%),TT 12(24%),CC 11(22%);ABCB1 2677T> G genotype distribution frequency was GT 24(48%),TT 19(38%),and GG 7(14%).The minimum allele frequencies of the four genotypes were A(27%),G(16%),C(49%),and G(38%).After genetic balance analysis,the SNP distribution of each genotype complied with Hardy-Weinberg equilibrium.3.Finally,a three-compartment model with first-order absorption and first-order linear elimination was established as the pharmacokinetic model of docetaxel.The final model formula for docetaxel is:.The population clearance for docetaxel is typically 41.3 L / hr.ABCB1 2677T> G gene is a genetic factor that affects docetaxel clearance.4.The graphical method shows that the final model is better than the basic model.Therobustness rate of the Bootstrap method is 95.1%,which indicates that the final model has high stability,and the visual prediction test shows that the final model has a good prediction ability.Conclusions:1.This study uses the latex immunoturbidimetric method to determine the blood drug concentration,which is simple,rapid,and suitable for clinical detection.2.The distribution of the four genotypes in the population and Hardy-Weinberg equilibrium are representative of the population.3.The docetaxel PPK model established in this study is stable and effective,which can provide scientific basis for individualized medication for clinical breast cancer.