两种伊马替尼制剂的人体生物等效性

目的建立人血浆中伊马替尼及其代谢物浓度的液相色谱-串联质谱法(LC-MS/MS)测定方法,并评价伊马替尼胶囊的药动学特征及生物等效性。方法 24名男性健康受试者随机分成两组,分别交叉给予伊马替尼受试制剂和参比制剂各400 mg,采用LC-MS/MS测定伊马替尼及伊马替尼代谢物的浓度,色谱柱为Thermo BDS HYPERSIL C18(100 mm×4.6 mm,2.4μm),流动相为甲醇(A)-0.1%甲酸0.2%醋酸铵溶液(B)(55:45,V/V),流速为0.7 mL·min-1;质谱采用电喷雾电离,正离子多离子反应监测模式,检测离子伊马替尼为m/z 494.10→393.85,伊马替尼代谢物为m/z 480.10→393.80,帕洛诺司琼(内标物)为m/z 297.10→109.80,估算伊马替尼及代谢物的药动学参数,评价两种制剂的人体生物等效性。结果伊马替尼受试制剂与参比制剂的各主要药动学参数:tmax分别为(2.8±1.2)h和(3.1±1.1)h,ρmax分别为(1 928.94±478.84) μg·L-1和(1 738.94±237.30) μg·L-1,t1/2分别为(17.65±1.71)h和(17.80±1.99)h,用梯形法计算AUC0-120 h分别为(37 715.80±7 625.84)μg.h.L-1和(33 961.65±6 218.64)μg.h.L-1,其代谢物的药动学参数:tmax分别为(2.8±1.2)h和(2.8±1.1)h,ρmax分别为(194.21±58.85) μg·L-1和(198.16±52.49) μg·L-1,t1/2分别为(37.59±3.53)h和(38.45±5.28)h,用梯形法计算AUC0-120 h分别为(5 274.57±1 379.87)μg.h.L-1和(5 128.31±1 119.75)μg.h.L-1。结论建立的测定方法可用于伊马替尼及其代谢物的药动学研究,伊马替尼两种制剂生物等效。

Bioequivalence of two kinds of imatinib preparations in healthy volunteers

AIM To establish a LC-MS/MS method for the determination of imatinib and its metabolite in human plasma and to evaluate the pharmacokinetics and bioequivalence of imatinib capsuls in healthy volunteers.METHODS A 400 mg dose of the reference or test capsules were given to 24 healthy male volunteers in a randomized two-way crossover design and the plasma concentration of the drug was assayed by LC-MS/MS.Chromatography separation was carried on a Thermo BDS HYPERSIL C18(100 mm × 4.6 mm,2.4 μm),with a mobile phase consisting of methanol-0.1% formic acid 0.2%ammonium acetate(55:45,V/V),a flow rate of 0.7 mL·min-1.Detection and quantification were performed by mass spectrometry in the multiple reaction monitoring mode with positive electrospray ionization at 494.10→393.85 for imatinib,480.10→393.80 for metabolite and 297.10→109.80 for palonosetron(internal standard),respectively.The main pharmacokinetic parameters and bioequivalence of the two formulations were evaluated.RESULTS The major pharmacokinetic parameters of the reference and test capsules were as follows:tmax(2.8 ± 1.2)h and(3.1 ± 1.1)h,ρmax(1 928.94 ± 478.84)μg·L-1 and(1 738.94 ± 237.30)μg·L-1,t1/2(17.65 ± 1.71)h and(17.80 ± 1.99)h,AUC0-120 h(37 715.80 ± 7 625.84)μg·h·L-1 and(33 961.65 ± 6 218.64)μg·h·L-1.The major pharmacokinetic parameters of their metabolites were as follows:tmax(2.8 ± 1.2)h and(2.8 ± 1.1)h,ρmax(194.21 ± 58.85)μg·L-1 and(198.16 ± 52.49)μg·L-1,t1/2(37.59 ± 3.53)h and(38.45 ± 5.28)h,AUC0-120 h(5 274.57 ± 1 379.87)μg·h ·L-1 and(5 128.31 ± 1 119.75)μg·h ·L-1,respectively.CONCLUSION The method was successful applied to pharmacokinetic study,of imatnib and its metabolite.The results showed that the two formulations were bioequivalent.