大剂量口服白消安在异基因造血干细胞移植预处理患者体内药动学研究

Pharmacokinetics of Oral Busulfan in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

目的研究异基因造血干细胞移植(allo-HSCT)预处理患者口服大剂量白消安(Bu)的药动学特征。方法allo-HSCT预处理患者口服Bu1mg·kg-1,q6h,共16剂。在首剂和第9剂给药时,分别于给药前及给药后不同时间点采集血样,用高效液相色谱法测定血浆Bu浓度;用DAS软件进行药动学房室模型拟合,计算药动学参数。结果首剂和第9剂给药后Bu在allo-HSCT预处理患者体内血药浓度-时间曲线均符合一室模型,其主要药动学参数分别为:t1/2(133.0±30.6)与(131.4±28.2)min,Ke(0.005±0.001)与(0.006±0.001)min-1,Vd/F(0.56±0.12)与(0.46±0.08)L·kg-1,CL/F(0.003±0.001)与(0.002±0.001)L·min-1·kg-1,AUC0-t(910.3±146.9)与(1158.5±139.0)μmol·min·L-1,AUC0-∞(1401.9±243.2)与(1689.0±312.4)μmol·min·L-1;Bu平均稳态血浆浓度为(3.29±0.39)μmol·L-1。结论口服大剂量Bu在allo-HSCT预处理患者体内过程符合一室药动学模型,主要药动学参数个体差异大,多次给药后药物清除率发生改变。

OBJECTIVE To study the pharmacokinetic profiles of oral busulfan in Chinese patients undergoing allogeneic hematopoietic stem cell transplantation. METHODS Blood samples of 9 adult patients were collected following the first and the ninth dose of standard 16 doses of oral busulfan, 4-day regimen. The plasma concentrations of busulfan were determined by HPLC, and the pharmacokinetic parameters of busulfan were calculated by DAS statistical software. RESULTS The plasma concentrationtime curves after dose 1 and dose 9 of oral 1 mg·kg^-1 busulfan in 9 patients were described by an one-compartment model, respectively. The main pharmacokinetic parameters were as follows： t1/2 （133.0±30.6） and （131.4±28.2） min, Ke （0.005±0.001） and （0.006±0.001）min^-1, Vd/F （0.56±0.12） and （0.46±0.08） L·kg^-1, CL/F （0.003±0.001） and （0.002± 0.001 ） L·min^-l·kg^-1, AUC0-t （910.3 ± 146.9） and （ 1 158.5±139.0） μmol·min·L^-1, AUC0_∞ （ 1 401.9±243.2） and （ 1 689.0±312.4） μmol·min·L^-1, respectively. Busulfan average steady state plasma concentration was （3.29±0.39） μmol·L^-1. CONCLUSION The pharmacokinetic profiles of oral busulfan are fitted to an one-compartment model, and the main pharmacokinetic parameters are significant difference between dose 1 and dose 9.