苹果酸舒尼替尼胶囊在中国健康受试者的生物等效性研究及食物对其药动学影响

Bioequivalence study of sunitinib malate formulations in Chinese healthy subjects and the effect of food on the pharmacokinetics of it

目的:评价受试制剂苹果酸舒尼替尼胶囊与原研制剂苹果酸舒尼替尼(索坦)的生物等效性,分析食物对舒尼替尼药动学的影响。方法:采用随机、开放、两周期、交叉试验设计。48例健康男性受试者被随机分配到空腹组(24例)或高脂餐组(24例),分别于每周期单剂量口服苹果酸舒尼替尼胶囊(12.5 mg)受试制剂(T)或参比制剂(R)。采用高效液相色谱串联质谱分析方法(HPLC-MS/MS)测定血浆中舒尼替尼浓度。用Phoenix WinNonlin 6.4计算药动学参数。结果:24例空腹组健康受试者口服受试制剂和参比制剂后的主要药动学参数:Cmax分别为(6.58±2.50)和(6.42±2.46) ng·mL^-1,Tmax分别为6.00(6.00,8.00)和6.00(6.00,10.00) h,AUC0-72h分别为(208.91±75.79)和(207.09±83.30) ng·h·mL^-1,AUC0-∞分别为(321.92±131.48)和(319.43±145.96) ng·h·mL^-1,t1/2分别为(53.70±13.93)和(52.04±12.02) h。受试制剂Cmax,AUC0-72h,AUC0-∞几何均数的90%置信区间分别落在参比制剂相应参数的97.38%~108.30%,99.01%~106.47%,99.12%~107.68%,均在80.00%~125.00%范围之间,符合生物等效性规定要求。24例高脂餐组健康受试者口服受试制剂和参比制剂后的主要药动学参数:Cmax分别为(5.48±1.61)和(5.58±1.77) ng·mL^-1,Tmax分别为8.00(6.00,14.00)和8.00(6.00,12.00) h,AUC0-72h分别为(195.01±65.24)和(189.06±60.10) ng·h·mL^-1,AUC0-∞分别为(281.55±106.64)和(272.06±95.53) ng·h·mL^-1,t1/2分别为(43.57±11.05)和(46.70±11.62) h。受试制剂Cmax,AUC0-72h,AUC0-∞几何均数的90%置信区间分别落在参比制剂相应参数的93.85%~103.88%,98.32%~107.43%,97.90%~107.91%,均在80.00%~125.00%范围内,符合生物等效性规定要求。与空腹比较,高脂高热餐后服用本品,Cmax降低14.9%,Tmax延长2 h,AUC0-72h及AUC0-∞分别降低7.7%和13.7%,终末半衰期缩短7.73 h。结论:受试制剂和参比制剂在中国健康男性受试者体内具有生物等效性。食物对舒尼替尼的药动学影响较小。

Objective: To assess the bioequivalence of sunitinib malate capsule with reference and the effect of food on the pharmacokinetics of sunitinib. Methods: A randomized, open-label, 2-period crossover study was conducted in 48 healthy Chinese male volunteers under fasted or fed conditions(24 volunteers for each condition). In each session, the subjects received a single oral dose of test(T) or reference(R) formulation of sunitinib malate capsule at 12.5 mg. Sunitinib concentrations in plasma were determined by a validated HPLC-MS/MS method. Pharmacokinetic parameters were calculated using a non-compartmental model through Phoenix WinNonlin version 6.4 and the bioequivalence was assessed. Results: The pharmacokinetic parameters of test and reference drug under fasted condition are: Cmax,(6.58±2.50) and(6.42±2.46) ng·mL^-1;Tmax, 6.00(6.00,8.00) and 6.00(6.00,10.00) h;AUC0-72 h(208.91±75.79) and(207.09±83.30) ng·h·mL^-1;AUC0-∞,(321.92±131.48) and(319.43±145.96) ng·h·mL^-1;t1/2,(53.70±13.93)and(52.04±12.02) h respectively. The 90% CIs for test:reference for Cmax, AUC0-72 h and AUC0-∞ were 97.38%~108.30%, 99.01%~106.47%, and 99.12%~107.68%, which were all within the range of 80.00%~125.00%. The two formulations tested were considered bioequivalent when administered under fasted condition to healthy adult subjects. The pharmacokinetic parameters of test drug and reference drug under fed condition are: Cmax,(5.48±1.61) and(5.58±1.77) ng·mL^-1;Tmax, 8.00(6.00,14.00)and 8.00(6.00,12.00) h;AUC0-72 h,(195.01±65.24) and(189.06±60.10) ng·h·mL^-1;AUC0-∞,(281.55±106.64)and(272.06±95.53) ng·h·mL^-1;t1/2,(43.57±11.05) and(46.70±11.62) h respectively. The 90% CIs for T/R for Cmax, AUC0-72 h and AUC0-∞ were 93.85%~103.88%, 98.32%~107.43%, and 97.90%~107.91%, which were all within the range of 80.00%~125.00%. The two formulations tested were considered bioequivalent when administered under fed condition to healthy adult subjects. Compared with fasted condition, taken high fat breakfast before administrated malate sunitinib, Cmax decreased by 14.9%, Tmax extended for 2 h, AUC0-72 h and AUC0-∞ were reduced 7.7% and 13.7%, respectively, t1/2 reduced by 7.73 h. Conclusion: This study suggest that the test formulation of sunitinib malate capsule is bioequivalent with the reference formulation in Chinese healthy male subjects. Food have little influence on the pharmacokinetic of sunitinib.