The Pharmacokinetics Of Docetaxel And Its Adverse Reaction In Chinese Breast Cancer Patients

Background and object:Docetaxel?DTX?,a semi-synthetic anticancer drugs,is widely used in treatment of breast cancer,non-small cell lung cacer and metastatic prostate cancer.DTX has a narrow therapeutic window.There is great individual difference in DTX pharmacokinetics and incidence of adverse reactions,which can be attributed to different pathophysiological factors.We studied the DTX pharmacokinetics and ADR in Chinese breast cancer patients,as well as the respective factors,which can provide useful information in the rational usage of DTX.Method:In the first part of the study,we established an LC-MS/MS method for the determination of DTX in human plasma and investigated the pharmacokinetic characteristics of DTX in 2 Chinese breast cancer patients who administered DTX at a dose of 75 mg·m^-2 i.v..In the second part,whole blood samples for a pharmacokinetic study were collected from 17 SD rats which administered DTX at a dose of 5 mg·kg^-1through jugular vein.DTX concentrations at pre-dose and 15 min,30 min,1 h,2 h,4 h,6h,12 h post-dose were determined by the method established and DTX pharmacokinetic characteristics were investigated.The concentration of unbound DTX was measured in the plasma ultrafiltrate at 15 min post-dose and the free fraction?fu?was calculated.AAG concentration in rat plasma was measured by enzyme-linked immunosorbent assay.In the third part,we collected the probability of grade 3⁴ neutropenia of 48 breast cancer patients administrated DTX.Then we detected polymorphism of CYP3A5,MDR1 C1236T,G2677T/A,C3435T,and ORM1.Fu and plasma AAG concentration were also determined.Results:In the first part of the study,the assay was linear in the range of 5.0¹000ng?mL^-1?r=0.9983??The lower quantitative limit of DTX was 5.0 ng?mL^-1.The intra-and inter-day RSD was below 15%.Whole blood samples for a pharmacokinetic study were collected from 2 breast cancer patients and DTX concentrations at 2,4,7,10,24,48 and72 h post-dose were determined by the method established.The pharmacokinetic parameters of 2 breast cancer patients were as follows:CL was 35.9 and 48.3 L·h^-1,t_1/2was 30.60 and 30.85 h,C_maxax was 157 and 143 ng?mL^-1,AUC_0-12 was 2091 and 1553ng·h·mL^-1,Vd was 1580/2150 L.In the second part,The pharmacokinetic parameters of DTX in rats were as follows:CL was?0.87±0.19?L·h^-1,t_1/2 was?4.90±1.01?h,Vd was?6.24±2.32?L,AUC_0??was?1041.11±272.91?ng·h·mL^-1.The concentration of unbound DTX was?80.97±6.19?ng?mL^-1 and fu was?16.83±0.71?%.When relationships between plasma concentrations of fu and DTX pharmacokinetics were investigated,fu was found to be positively correlated with CL?r=0.763,p<0.05?,and negatively correlated with AUC₀?₁₂?r=-0.715,p<0.05?,AUC0???r=-0.755,p<0.05?.When relationships between plasma concentrations of AAG and DTX pharmacokinetic were investigated,AAG was found to be negatively correlated with CL?r=-0.712,p<0.05?,and positively correlated with AUC0?₁₂?r=0.671,p<0.05?,AUC0???r=0.686,p<0.05?.In the third part,the probability of grade 3⁴ neutropenia of 48 breast cancer patients administrated DTX was 31.25%.When the influence of genetic polymorphism,fu and plasma AAG concentration on grade 3⁴ neutropenia was investigated in breast cancer patients,CYP3A5*1/*3 genotype have a 3.01-fold higher risk of grade 3⁴ neutropenia than*3/*3genotype?95%CI=1.13⁸.02,P=0.014?,ORM1*S/*S genotype have a 3.05-fold risk of grade 3⁴ neutropenia than other genotypes?95%CI=1.24⁷.54,p=0.01?.Conclusion:The method established is rapid,sensitive,accurate and reliable for the determination of docetaxel in plasma of breast cancer patients.We found fu of DTX in rats plasma was be positively correlated with CL and negatively correlated with AUC.We also found concentrations of AAG in rats plasma was negatively correlated with CL and positively correlated with AUC.Breast cancer patients carrying ORM1*S/*S genotype have a significan higher risk of grade 3⁴ neutropenia than other genotypes,which was first discoverd,and CYP3A5*1/*3 genotype have a significan higher risk of grade 3⁴neutropenia than*3/*3 genotype.