阿莫西林克拉维酸钾片在健康受试者体内的生物等效性研究

Bioequivalence of amoxicillin clavulanate potassium tablet in healthy volunteers

目的研究健康受试者空腹和餐后条件下单次口服阿莫西林克拉维酸钾片受试制剂和参比制剂是否具有生物等效性。方法用单剂量、随机、开放、四周期、自身交叉设计。空腹及餐后试验均按照1∶1比例随机分为2个给药顺序组,分别口服阿莫西林克拉维酸钾片受试制剂或参比制剂375 mg,用液相色谱串联质谱法测定给药后血浆中阿莫西林和克拉维酸的药物浓度,用Phoenix WinNonlin 8.2软件进行药代动力学参数计算及生物等效性评价。结果受试者单次空腹口服受试制剂和参比试剂后,阿莫西林的主要药代动力学参数如下:C_(max)分别为(5075.57±1483.37)和(5119.86±1466.73)ng·mL^(-1),AUC_(0-t)分别为(1.32×10^(4)±2163.76)和(1.30×10^(4)±1925.11)ng·mL^(-1),AUC_(0-∞)分别为(1.32×10^(4)±2175.40)和(1.31×10^(4)±1935.86)ng·mL^(-1);克拉维酸的主要药代动力学参数如下:C_(max)分别为(3298.27±1315.23)和(3264.06±1492.82)ng·mL^(-1),AUC_(0-t)分别为(7690.06±3053.40)和(7538.39±3155.89)ng·mL^(-1),AUC_(0-∞)分别为(7834.81±3082.61)和(7671.67±3189.31)ng·mL^(-1)。2种制剂的阿莫西林和克拉维酸的C_(max)、AUC_(0-t)和AUC_(0-∞)经对数转换后的90%可信区间均在80.00%~125.00%内。受试者单次餐后口服受试制剂和参比试剂后,阿莫西林的主要药代动力学参数如下:C_(max)分别为(4514.08±1324.18)和(4602.82±1366.48)ng·mL^(-1),AUC_(0-t)分别为(1.15×10^(4)±1637.95)和(1.15×10^(4)±1665.69)ng·mL^(-1),AUC_(0-∞)分别为(1.16×10^(4)±1646.26)和(1.15×10^(4)±1607.20)ng·mL^(-1);克拉维酸的主要药代动力学参数如下:C_(max)分别为(2654.75±1358.29)和(2850.51±1526.31)ng·mL^(-1),AUC_(0-t)分别为(5882.82±2930.06)和(6161.28±3263.20)ng·mL^(-1),AUC_(0-∞)分别为(6022.70±2965.05)和(6298.31±3287.63)ng·mL^(-1)。2种制剂的阿莫西林和克拉维酸的C_(max)、AUC_(0-t)和AUC_(0-∞)经对数转换后的90%可信区间均在80.00%~125.00%内。结论健康成年受试者在空腹和餐后条件下,单次口服受试制剂和参比制剂具有生物等效性。

Objective To evaluate the bioequivalence of test product and reference product in a single dose of amoxicillin clavulanate potassium tablet under fasting and fed conditions in healthy volunteers.Methods An open label,randomized,single dose,four-period,crossover bioequivalence study was designed.Fasting and postprandial tests were randomly divided into 2 administration sequence groups according to 1∶1 ratio,amoxicillin clavulanate potassium tablet test product or reference product 375 mg,oral administration separately,liquid chromatography tanden mass spectrometry was applied to determine the concentration of amoxicillin and clavulanate potassium in plasma of healthy subjects after fasting or fed administration,while Phoenix WinN onlin 8.2 software were used for pharmacokinetics (PK) parameters calculation and bioequivalence analysis.Results Healthy subjects took the test product and the reference product under fasting condition,the main PK parameters of amoxicillin are as follows:C_(max) were (5 075.57±1 483.37) and (5 119.86±1 466.73) ng·mL^(-1),AUC_(0-t)were (1.32×10^(4)±2 163.76) and(1.30×10^(4)±1 925.11) ng·mL^(-1),AUC_(0-∞)were (1.32×104±2 175.40) and (1.31×10^(4)±1 935.86) ng·mL^(-1);the main PK parameters of clavulanic acid are as follows:C_(max)were (3 298.27±1 315.23) and (3 264.06±1 492.82) ng·mL^(-1),AUC_(0-t)were (7 690.06±3 053.40) and (7 538.39±3 155.89) ng·mL^(-1),AUC_(0-∞)were (7 834.81±3 082.61)and (7 671.67±3 189.31) ng·mL^(-1);the 90%confidence intervals of C_(max),AUC_(0-t)and AUC_(0-∞)after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00%-125.00%.Healthy subjects took the test and reference product under fed condition,the main PK parameters of amoxicillin are as follows:C_(max)were (4 514.08±1 324.18) and (4 602.82±1 366.48) ng·mL^(-1),AUC_(0-t)were (1.15×10^(4)±1 637.95) and(1.15×10^(4)±1 665.69) ng·mL^(-1),AUC_(0-∞)were (1.16×10^(4)±1 646.26) and (1.15×10^(4)±1 607.20)ng·mL^(-1);the main PK parameters of clavulanic acid are as follows:C_(max)were (2 654.75±1 358.29) and(2 850.51±1 526.31) ng·mL^(-1),AUC_(0-t)were (5 882.82±2 930.06) and (6 161.28±3 263.20) ng·mL^(-1),AUC_(0-∞)were (6 022.70±2 965.05) and (6 298.31±3 287.63) ng·mL^(-1);the 90%confidence intervals of C_(max),AUC_(0-t)and AUC_(0-∞)after logarithmic conversion of amoxicillin and clavulanate potassium of the two products were all within 80.00%-125.00%.Conclusion The two formulations were bioequivalent to healthy adult volunteers under fasting and fed conditions.