匹伐他汀钙片单、多剂量人体药动学评价

Pharmacokinetics of Pitavastatin with Single and Multiple-dose in Chinese Healthy Volunteers

目的:建立LC-MS/MS法测定人血浆中匹伐他汀的浓度,研究其在中国健康受试者体内的单、多剂量药动学过程。方法:20名健康志愿者随机分为2组,每组10人(男女各半),分别口服低、中、高3个剂量(1,2,4 mg)进行单剂量药动学研究,2 mg剂量组继续给药(每日1次,连续7 d),进行多剂量药动学研究。采用LC-MS/MS法测定血浆中匹伐他汀的浓度,并采用WinNonLin 6.2计算药动学参数。结果:健康受试者单剂量口服1、2、4 mg匹伐他汀钙片后的药动学参数:t_(1/2)分别为(11.29±4.28)h、(13.52±5.65)h和(11.87±2.87)h;t_(max)分别为(0.78±0.32)h、(0.75±0.17)h和(0.93±0.31)h;C_(max)分别为(15.80±7.34)ng·ml^(-1)、(36.54±6.29)ng·ml^(-1)和(61.32±15.09)ng·ml^(-1);AUC_(0-48)分别为(36.46±21.86)ng·h·ml^(-1)、(107.90±28.55)ng·h·ml^(-1)和(187.76±62.62)ng·h·ml^(-1);AUC_(0-∞)分别为(40.91±23.20)ng·h·ml^(-1)、(112.97±29.08)ng·h·ml^(-1)和(197.55±68.51)ng·h·ml^(-1)。多剂量组口服2 mg匹伐他汀后的药动学参数:t_(1/2)为(13.07±2.16)h,t。。为(0.68±0.12)h,C★;为(33.88±6.91)ng·ml～,AUC,:为(68.21±20.82)ng·h·ml～,AUC(048)为(77.78±±26.50)ng·h·ml～,AUC(0.。)为(82.59±26.58)ng·h·ml～。匹伐他汀钙多次给药达稳态后,药动学参数t～、t1/2与单次给药一致。结论:在1～4 mg剂量范围内匹伐他汀的AUC(。。8)、AUC(吣)、C～均与剂量呈线性关系;匹伐他汀在连续多次给药后,无体内蓄积现象;匹伐他汀的体内过程在男女性别间无显著差异。

Objective： To develop an LC-MS/MS method for the analysis of pitavastatin in human plasma and study the pharmacokinetics of pitavastatin with single and multiple dose in healthy volunteers. Method： Thirty healthy volunteers were randomly divided into three groups with 5 males and 5 females in each group. The volunteers in the three groups were orally given pitavastatin with single dose 1,2 and 4 mg, respectively, and those with the dose of 2 mg were orally administrated once a day for seven days. The plasma concentrations of pitavastatin were determined by LC-MS/MS method, and its pharmacokinetic parameters were calculated and analyzed by WinNonLin 6.2. Result： The main pharmacokinetic parameters of a single-dose （ 1,2 and 4 mg） pitavastatin were as follows： tl/2 of（11.29±4.28）h,（13.52±5.65）hand （11.87±2.87）h, tmaxof（0.78±0.32）h, （0.75±0.17）hand （0.93 ±0.31）h, C18 of（ 15.80 ± 7.34） ng · ml - 1, （36.54 ±6.29 ） ng· ml - l and （ 61.32 ± 15.09 ） ng · ml - 1 ,AUC0-48 of（ 36.46 ±21.86 ） ng· h ·ml - 1 , （107.90±28.55）ng. h· ml-1 and（187.76±62.62）ng, h · ml-1, AUC（0-m） of（40.91 ±23.20）ng · h · ml-1,（112.97 ±29.08 ） ng · h · m1-1 and （ 197.55 ± 68.51 ） ng - h · ml -1, respectively. The main pharmacokinetie parameters of mutiple-dose （ 2 mg） pitavastatin were as follows： t1/2 of（ 13.07±2.16）h, t1/2 of（0.68 ± 0.12）h, Cmax of（33.88 ± 6.91 ）ng · ml-1, A UC,s of（68.21 ±20.82）ng· h · ml-1, AUC0-48 of （77.78 ±26.50）ng· h · ml-1 and AUC（0-m） of（82.59 ±26.58） ng · h · ml-1. Conclusion： No accumulation occurs after the administration of multiple-dose pitavastatin. AUC（0-48） , AUC（0- ∞） and Cmax are increased with the dosage increase of pitavastatin, showing no significant difference in physiological disposition between the male and the female.