匹伐他汀片在中国健康人体的单、多剂量药动学

Pharmacokinetics of single and multi-dose pitavastatin calcium tables in healthy volunteers

目的建立快速、灵敏的匹伐他汀人体内血药浓度的液相色谱-质谱测定法,研究匹伐他汀片在中国健康人体内的单、多剂量药动学。方法 30名健康志愿者随机分为3组,每组10人(男女各半),分别口服匹伐他汀低、中、高3个剂量(1 mg、2 mg、4 mg)进行单剂量药动学研究,2 mg剂量组继续给药(每天1次,连续7 d),进行多剂量药动学研究。采用HPLC-MS/MS法测定血浆中匹伐他汀的浓度,并采用PKS程序对试验数据进行处理,求算有关药动学参数。结果健康受试者单剂量给药1、2、4 mg匹伐他汀后主要的药动学参数:Cmax(30.89±11.05)μg.L-1、(74.02±35.71)μg.L-1、(123.70±26.37)μg.L-1;Tmax(0.78±0.18)h、(0.73±0.25)h、(0.70±0.16)h;T1/2(9.80±3.33)h、(10.81±1.96)h、(12.79±3.00)h;AUC0-48(90.51±31.10)μg.h.L-1、(225.89±82.71)μg.h.L-1、(350.15±70.25)μg.h.L-1;AUC0-∞(93.72±32.72)μg.h.L-1、(232.15±86.22)μg.h.L-1、(365.39±75.46)μg.h.L-1。中剂量组10名受试者多次口服受试药2 mg后主要药动学参数:Cmax(80.26±19.43)μg.L-1;Tmax(0.75±0.29)h;T1/2(10.76±1.96)h;AUC0-48(270.53±98.44)μg.h.L-1;AUC0-∞(280.55±104.97)μg.h.L-1;波动度DF为(8.21±2.11)%。结论匹伐他汀在连续多次给药后,体内无蓄积现象,血药浓度第5天已达稳态。匹伐他汀的剂量与Cmax、AUC0-∞和AUC0-24呈正相关关系;匹伐他汀的体内过程在男女性别间差异无显著性。匹伐他汀片单、多剂量给药后在中国健康人体内的药动学行为与国外文献报道基本一致。

Objective To develop a rapid and sensitive HPLC-MS method for the analysis of pitavastatin in human plasma and study on the pharmacokinetics of pitavastatin calcium tables with single and multiple dose in healthy volunteers. Methods Thirty healthy volunteers were randomly divided into three groups with 5 males and 5 females in each group.The volunteers in three groups were administrated with single dose pitavastatin 1,2,4 mg respectively,and those who got 2 mg were administrated once a day for seven days.Blood samples were collected according to the protocol and serum concentrations of pitavastatin were assayed by HPLC-MS/MS.PKS pharmacokinetic program was performed to calculate pharmacokinetics parameters.Results The main pharmacokinetics parameters of pitavastatin volunteers administrated with a single dose of 1,2,4 mg were as follows：Cmax（30.89±11.05）μg·L-1、（74.02±35.71）μg·L-1、（123.70±26.37）μg·L-1;Tmax（0.78±0.18）h、（0.73±0.25）h、（0.70±0.16）h;T1/2（9.80±3.33）h、（10.81±1.96）h、（12.79±3.00）h;AUC0-48（90.51±31.10）μg·h·L-1、（225.89±82.71）μg·h·L-1、（350.15±70.25）μg·h·L-1;AUC0-∞（93.72±32.72）μg·h·L-1、（232.15±86.22）μg·h·L-1、（365.39±75.46）μg·h·L-1 respectively.The main pharmacokinetic parameters of pitavastatin after multiple-dose（2mg） administration were as follows：Cmax（80.26±19.43）μg·L-1;Tmax（0.75±0.29）h;T1/2（10.76±1.96）h;AUC0-48（270.53±98.44）μg·h·L-1;AUC0-∞（280.55±104.97）μg·h·L-1;DF（8.21±2.11）%.Conclusion After administration of multiple-dose pitavastatin,no accumulate occur in vivo.Serum concentrations of pitavastatin have been in steady state till fifth day.Cmax、AUC0-∞ and AUC0-24 increase along with pitavastatin dosage positively with no significant difference of physiological disposition between the male and female.The pharmacokinetic characteristics of pitavastatin calcium tables were consistent with foreign reports.