阿维莫泮在中国健康受试者中的药动学研究

目的: 研究在中国健康志愿者中单次及多次口服阿维莫泮胶囊后阿维莫泮及其代谢产物ADL 08-0011的药动学特征。方法: 共入组24例受试者,其中12例受试者参加6、12、18 mg 3个剂量组单次给药药动学研究,采用随机开放、3×3拉丁方试验设计;在完成3个周期的单次试验后,继续进行连续多次给药药动学试验,给药方法为每天给药2次,每次给药 12 mg,共给药 6 d。另外12例受试者参加 24 mg 剂量单次给药药动学研究。采用LC-MS/MS法测定人血浆中阿维莫泮及代谢产物ADL08-0011浓度,应用WinNonlin 6.1软件计算药动学参数。结果: 阿维莫泮在 0.192~75 μg/L 范围线性良好,特异性、精密度、准确度及回收率都符合生物样本测试要求。6、12、18、24 mg 单次给药的主要药动学参数如下: C_max(8.79±6.10)、(18.30±9.92)、(31.48±13.68)、(32.91±17.95) μg/L;t_max(1.4±0.6)、(1.8±0.6)、(1.8±0.6)、(2.1±0.6) h;AUC_last(33.2±23.0)、(60.3±28.9)、(94.1±42.2)、(112.0±57.5 ) μg·h·L^-1; t_1/2(8.4±4.9)、(8.4±5.3)、(7.9±4.8)、(10.0±4.3) h; CL/F(218.1±111.8)、(234.7±135.7)、(217.6±95.3)、(256.9±132.5) L/h。多次给药(12 mg bid)的主要药动学参数如下:C_max (16.57±10.15) μg/L,t_max(1.6±1.0) h,AUC_last (64.4±32.0) μg·h·L^-1,t_1/2 (12.0±3.3) h,CL/F (258.4±109.4) L/h。结论: 该方法准确灵敏,适用于阿维莫泮的药动学研究。阿维莫泮在6~18 mg 剂量范围内的单次给药以及 12 mg bid 的多次给药人体药动学特征都符合线性动力学过程,而 24 mg 剂量单次给药则吸收过程出现非线性动力学过程。

Pharmacokinetics of Alvimopan capsules in healthy Chinese volunteers

AIM: To study the pharmacokinetics of Alvimopan and its metabolite ADL 08-0011 in Chinese healthy volunteers after single and multiple oral administrations of Alvimopan capsules.METHODS: This study contains 24 healthy adult subjects totally. 12 healthy adult subjects (6 males, 6 females) were randomly grouped by 3×3 Latin square. Three single doses of Alvimopan capsules, 6 mg, 12 mg, 18 mg, were given to each group at each period to make each group take each dose once after three periods. After three periods, the 12 subjects were given multiple doses of Alvimopan capsules at 12 mg (bid) for 6 days.The resting 12 subjects were given single highest dose of 24 mg. The plasma concentrations of Alvimopan and ADL08-0011 were measured by a validated LC-MS/MS method and the pharmacokinetic parameters were calculated using WinNonlin 6.1.RESULTS: The linear range of Alvimopan was 0.192-75 μg/L(r=0.9986). Results of methodology validation-specificity, precision,accuracy and average recovery-fit the requirements of sample determination. The main pharmacokinetic parameters of Alvimopan after single dose administration (6, 12, 18 and 24 mg) were C_max: (8.79±6.10), (18.30±9.92), (31.48±13.68) and (32.91±17.95) μg/L; T_max: (1.4±0.6), (1.8±0.6), (1.8±0.6) and(2.1±0.6) h; AUC_last:(33.2±23.0), (60.3±28.9), (94.1±42.2) and (112.0±57.5)μg·h·L^-1; t_1/2: (8.4±4.9), (8.4±5.3), (7.9±4.8) and (10.0±4.3) h; CL/F: (218.1±111.8), (234.7±135.7), (217.6±95.3) and (256.9±132.5) L/h. Multiple administration (12 mg bid)pharmacokinetic parameters were: C_max: (16.57±10.15) μg/L, T_max : (1.6±1.0) h, AUC_last: (64.4±32.0) μg·h·L^-1, t_1/2 : (12.0±3.3) h and CL/F (258.4±109.4) L/h.CONCLUSION: Determination method is convenient, sensitive and suitable for the pharmacokinetics investigation. The pharmacokinetics of Alvimopan in Chinese healthy volunteers exhibits linear behavior in dose range of 6 - 18 mg. But pharmacokinetic nonlinearity was observed when dose up to 24 mg.