氨柔比星及氨柔比星醇在小细胞肺癌患者的药代动力学

Pharmacokinetics of amrubicin and amrubicinol in small cell lung cancer patients

目的评价中国小细胞肺癌患者中单次给药和多次给药后氨柔比星及其活性代谢产物氨柔比星醇的药代动力学特征。方法用多中心、开放、单次和多次给药的试验设计。12例广泛期小细胞肺癌患者,每日静脉推注盐酸氨柔比星40 mg·m-2,连续3 d,并在第1 d静脉输注顺铂60 mg·m-2。用LC-MS/MS法测定原型药物和活性代谢产物在血浆、全血和血细胞中的浓度,用WinNonlin非房室模型计算药代动力学参数。结果单次和多次给药后,氨柔比星的主要药代动力学参数,乙二胺四乙酸三钾(EDTAK3)抗凝血浆:cmax分别为(3460±1273),(4080±1895)ng·mL-1,AUC0-t分别为(2050±408),(2190±411)h·ng·mL-1;肝素抗凝血浆:cmax分别为(3660±1382),(4360±2065)ng·mL-1,AUC0-t分别为(2100±363),(2220±404)h·ng·mL-1;全血:cmax分别为(3240±1133),(3920±1582)ng·mL-1,AUC0-t分别为(2150±465),(2560±853)h·ng·mL-1;血细胞:cmax分别为(2100±544),(2500±796)ng·mL-1,AUC0-t分别为(2030±465),(2340±653)h·ng·mL-1。氨柔比星醇的主要药代动力学参数,EDTAK3抗凝血浆:cmax分别为(18.2±3.3),(30.1±3.8)ng·mL-1,AUC0-t分别为(258±43),(992±182)h·ng·mL-1;肝素抗凝血浆:cmax分别为(17.9±3.8),(30.9±5.7)ng·mL-1,AUC0-t分别为(259±51),(978±190)ng·h·mL-1;全血:cmax分别为(50.3±12.8),(81.9±19.3)ng·mL-1,AUC0-t为分别(723±198),(2610±656)h·ng·mL-1;血细胞:cmax分别为(83.6±19.9),(153.0±25.2)ng·mL-1,AUC0-t分别为(1290±319),(4400±831)h·ng·mL-1。结论氨柔比星醇在多次给药后发生蓄积,蓄积程度与文献报道的日本人相同,单次和多次给药后的血浆AUC0-24与日本人近似,血细胞cmax与日本人相似,但血浆cmax呈低于日本人的趋势。

Objective To evaluate the pharmacokinetics characters of amrubicin and its active metabolite amrubicinol following single and mul- tiple administrations in Chinese small cell lung cancer patients. This study was designed as a multi -center, open label, single and multiple doses study. Twelve patients with extensive stage small cell lung cancer were given iv as amrubicin hydrochloride 40 mg · m-2 for 3 days qd and cisplatin 60 mg · m-2 at day 1. Concentration of amrubicin and amrubicinol in plasma, blood and blood cell were analyzed by LC -MS/ MS. WinNonlin was used to calculate the pharmacokinetics parameters. Results Following single - and multiple - administration of amrubicin hydrochloride, and multiple - administration of amrubicin hydrochloride, for amrubicin, eathylene diamine tetra - acetic acid - K3 （ EDTAK3 ） anticoagulant plasma： Cmax was （3460 ± 1273 ） and （4080 ± 1895） ng · mL-1 , AUCo-1 was （2050 ±408） and （2190 ±412） h · ng · mL-l; heparin anticoagulant plas- ma： Cmax was （3660 ±1382） and （4360 ±2065） ng · mL-1, AUC0-1 was （2100 ±363） and （2220 ±404） h ·ng · mL-1 ; whole blood： Cmax was （3240 ± 1133） and （3920 ± 1582） ng ·mL-1 , AUC0_twas （2150 ±465） and （2560 ± 853） and. mL-1; blood cell： Cmax was （2100 ±544） and （2500 ±796） ng-mL-1 ,AUC0-1 was （2030 ±465） and （2340 ±653） h·ng· mL-1, respectively. For amrubicinol, EDTAK3 anticoagulant plasma： Cma was （18.2 ±3.3） and （30. 1 ±3.8） ng · mL-1, AUC0-1, was （258 ±43） and （992 ± 182） h · ng · mL-1; heparin anticoagulant plas- ma： Cmax was （17.9 ±3. 8） and （30. 9 ±5.7） ng · mL-1 , AUC0-1, was （259 ±51） and （978 ± 190） h · ng · mL-1 ; whole blood： Cmax was （50.3 ± 12. 8） and （81.9 ± 19. 3） ng · mL-1 ,AUC0-1was （723 ± 198） and （2610 ±656） h · ng · mL-l; blood cell： Cmax was （83.6 ±19.9） and （153.0 ±25.2） ng · mL-1, AUC0_t was （1290 ±319） and （4400 ± 831 ） h · ng · mL-l, respectively. Conclusion Anrrubicinol shows an accumulation after multiple administration, which is similar to Japanese by reported; plasma AUC0-24 is also similar to Japanese after single and multiple administrations; Cmax of arrtrubicinol in blood cells are comparable to Japanese patients, but cmax in plasma tends to be lower.