健康男性口服三种左旋多巴给药方案达稳态后的药动学及生物等效性试验

Study on the Steady-State Pharmacokinetics and Bioequivalence of Three Oral Compound Levodopa Preperations in Healthy Male Volunteers

目的评价中国男性志愿者口服3种左旋多巴给药方案后的人体稳态药动学和生物等效性。方法采用液相色谱-质谱/质谱法测定18名健康受试者口服3种左旋多巴制剂后血浆中的左旋多巴浓度。采用WinNonlin药动软件计算药动学参数,并评价其生物等效性。结果卡左双多巴控释片+恩他卡朋片(测试药1)、多巴丝肼片+恩他卡朋片(测试药2)和卡左双多巴控释片(参比药)的左旋多巴药动学参数AUC0-12分别为(3 657.57±683.27)、(2 365.87±597.81)和(3 017.48±612.99)ng.h.mL-1,实测ρmax为(809.56±128.40)、(742.50±152.81)和(746.83±148.53)ng.mL-1,实测tmax为(2.53±0.50)、(1.42±0.70)和(2.19±0.71)h,MRT0-inf为(6.57±2.15)、(6.04±1.91)和(6.75±2.80)h,t1/2为(2.96±1.04)、(2.72±1.43)和(2.87±1.12)h。以左旋多巴计,测试药1和测试药2与参比药的相对生物利用度分别为(128.77±47.69)%和(80.43±20.11)%。结论经统计学分析,以左旋多巴计,测试药1、测试药2分别和参比药相比均生物不等效。测试药1、测试药2与参比药的ρmax均生物等效。经非参数秩和检验,与参比药相比,测试药1的tmax无显著差异(P>0.05),测试药2有显著差异(P<0.05),参比药tmax大于测试药2的tmax。

OBJECTIVE To evaluate the steady-state pharmacokinetics and the bioequivalence of 3 oral compound levodopa preparations in 18 Chinese healthy male volunteers. METHODS Multiple oral doses of 3 compound levodopa preperations, i.e. test 1 ： Sinemet CR tablet and entacapone tablet, test 2 ： Madopar tablet and entacapone tablet, and reference ： Sinemet CR tablet, were given to 18 healthy volunteers in a randomized crossover study. The concentrations of levodopa were determined by HPLC-MS/MS method. RESULTS The main pharrnacokinetic parameters of the 3 preparations were as follows ： AUC0.,2 （3 657. 57 ± 683.27）, （2 365.87 ± 597.81 ） and （3 017.48 ±612. 99）ng . h . mL-1 ,pmax （809. 56 ±128.40）, （742. 50 ±152. 81 ）and （746. 83 ± 148.53） ng . mL-1 , tmax（2.53±0.50）, （1.42 ±0.70）and （2. 19 ±0.71） h, MRT0-inf （ 6. 57 ±2.15）, （6.04 ±1.91）and （6.75 ±2.80） h ,t1/2 （2. 96 ± 1.04）, （2. 72 ± 1.43 ） and （2. 87 ± 1.12） h, respectively. The relative bioavailability of test 1 and test 2 tablets to reference tablets were （ 128.77 ± 47.69 ） % and（ 80. 43± 20. 11 ） %, respectively. There were significant differences in the main pharmacokinetic parameters between the 3 preparations （P 〈 0. 05）. CONCLUSION The results of statistical analysis demonstrated that the relative bioavailability of two test preparations were nonbioequivalent to the reference one, but their pmax were both bioequivalent to the reference tablets, and the tmax, of test 1 had no difference with the reference （ P 〉 0.05 ）, the tmax of the reference was greater than the one of test 2 （P〈0.05） .