阿托伐他汀钙及其主要代谢物在中国健康成年男性中的药代动力学和生物等效性研究
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摘要
目的研究阿托伐他汀钙片仿制药与原研药在中国健康男性中单剂量空腹给药的药代动力学和生物等效性,为临床使用和一致性评价提供依据。方法采用空腹给药、半重复、三周期、交叉、参比药物校正的平均生物等效性试验(RSABE)设计,共纳入36例健康男性受试者,随机分为3组进行重复服用参比药物、三周期、交叉试验,每周期单剂量口服阿托伐他汀钙片20 mg,给药前和给药后按时采集静脉血,以HPLC-MS/MS法测定血浆中阿托伐他汀、邻羟基阿托伐他汀、对羟基阿托伐他汀的浓度,用Win Nonlin 6. 3计算药代动力学参数并进行生物等效性评价。结果阿托伐他汀AUC_(0-t)、AUC_(0-∞)均CV_(WR)<30%,用ABE的判断标准,受试药物与参比药物药代动力学(PK)参数几何均数平均值(GMR)估计值的90%置信区间分别为94. 8%～104. 4%和94. 9%～104. 5%,均不超出80. 0%～125. 0%; C_(max)的CV_(WR)> 30%,用RSABE的判断标准,critbound=-0. 049 <0,pointest=0. 94不超出0. 80～1. 25,可以判断受试药物和参比药物的阿托伐他汀具有生物等效性。邻羟基阿托伐他汀和对羟基阿托伐他汀的AUC_(0-t)、AUC_(0-∞)和C_(max)的GMR点估计值均在80. 0%～125. 0%,可进一步支持受试药物和参比药物具有生物等效性的判断。结论国产阿托伐他汀钙片和进口阿托伐他汀钙片药代动力学生物等效。
Objective To compare the pharmacokinetics and bioequivalence of atorvastatin calcium tablets test products and reference producets in healthy male Chinese subjects after single oral administration.Methods This was a fasting,three-period partial replicate,crossover,reference-scaled average bioequivalence study. A total of 36 subjects were randomly assigned to three groups to receive 20 mg reference products twice and test products once in three periods. The blood samples were collected before and after dosing,and atorvastatin,ortho-hydroxy-atorvaststin( o-OAT),para-hydroxy-atorvaststin( p-OAT) plasma concentrations were determined using HPLC-MS/MS. The pharmacokinetics parameters were calculated by WinNonlin 6. 3 software.Results The CV_(WR) for AUC_(0-t) and AUC_(0-∞) of atorvastatin were below30%, 90% confidence intervals of GMR point estimate were94. 8%-104. 4% and 94. 9%-104. 5% respectively,within the range of 80%-125. 0% according to ABE criteria. The CV_(WR) for C_(max) of atorvastatin was above 30%,critbound =-0. 049< 0,pointest = 0. 94 within the range of 0. 80-1. 25 according to RSABE criteria. The results demonstrated the atorvastatin between reference and test products are bioequivalent. The GMR point estimates of AUC_(0-t),AUC_(0-∞) and C_(max) of o-OAT and p-OAT were all within 80. 0%-125. 0%,which further approved that the two products were bioequivalent. Conclusion The results demonstrated that the test products and reference products were bioequivalent.
Objective To compare the pharmacokinetics and bioequivalence of atorvastatin calcium tablets test products and reference producets in healthy male Chinese subjects after single oral administration.Methods This was a fasting,three-period partial replicate,crossover,reference-scaled average bioequivalence study. A total of 36 subjects were randomly assigned to three groups to receive 20 mg reference products twice and test products once in three periods. The blood samples were collected before and after dosing,and atorvastatin,ortho-hydroxy-atorvaststin( o-OAT),para-hydroxy-atorvaststin( p-OAT) plasma concentrations were determined using HPLC-MS/MS. The pharmacokinetics parameters were calculated by WinNonlin 6. 3 software.Results The CV_(WR) for AUC_(0-t) and AUC_(0-∞) of atorvastatin were below30%, 90% confidence intervals of GMR point estimate were94. 8%-104. 4% and 94. 9%-104. 5% respectively,within the range of 80%-125. 0% according to ABE criteria. The CV_(WR) for C_(max) of atorvastatin was above 30%,critbound =-0. 049< 0,pointest = 0. 94 within the range of 0. 80-1. 25 according to RSABE criteria. The results demonstrated the atorvastatin between reference and test products are bioequivalent. The GMR point estimates of AUC_(0-t),AUC_(0-∞) and C_(max) of o-OAT and p-OAT were all within 80. 0%-125. 0%,which further approved that the two products were bioequivalent. Conclusion The results demonstrated that the test products and reference products were bioequivalent.
引文
[1]柯元南.阿托伐他汀治疗高脂血症的疗效和安全性[J].中华心血管病杂志,2001,29(3):132-135.
[2] REBECCA G,BAKKER A,DAVIDSON MH,et al. Efficacy and safety of a new HMG-CoA reductase inhibitor,atorvastatin,in patients with hypertriglyceridemia[J]. JAMA,1996,275(2):128-133.
[3] PFIZER. LIPITOR(atorvastatin calcium)Tablets for Oral Administration[EB/OL]. Maryland:FDA,2018-08-10[2019-03-20]. https://www. accessdata. fda. gov/drugsatfda_docs/label/2018/020702s071lbl. pdf.
[4] YANG Y,XU Q,ZHOU L,et al. High-throughput salting-out-assisted liquid-liquid extraction for the simultaneous determination of atorvastatin, ortho-hydroxyatorvastatin, and parahydroxyatorvastatin in human plasma using ultrafast liquid chromatography with tandem mass spectrometry[J]. J Sep Sci,2015,38(6):1026-1034.
[5] OFFICE OF GENERIC DRUGS,FDA. Draft guidance for industry on bioequivalence recommmendations for progesterone capsules[EB/OL]. Maryland:FDA,2011-02-12[2018-04-12].https://www. fda. gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM209294. pdf.
[6]刘东阳,李丽,江骥,等.高变异药物的生物等效性研究进展[J].中国临床药理学杂志,2008,24(4):339-343.
[7]刘曼,张丹,王晓琳,等.高变异药品及其参比制剂校正的平均生物等效性试验的探讨[J].中国新药杂志,2014,23(3):257-260.
[8]黄钦,魏春敏.浅谈高变异药物的生物等效性研究[J].中国临床药理学与治疗学,2007,12(8):841-844.
[9] HAIDAR S H,DAVIT B,CHEN M L,et al. Bioequivalence approaches for highly variable drugs and drug products[J]. Pharm Res,2008,25(1):237-241.
[10] EUROPEAN MEDICINES AGENCY(EMA). Committee for medicinal products for human use,CHMP. Guidance on the investigation of bioequivalence[EB/OL]. London:EMA,2010-08-01[2018-04-12]. http://www. ema. europa. eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039. pdf.
[11] HAIDAR S H,MAKHLOUF F,SCHUIRMANN D J,et al. Evaluation of a scaling approach for the bioequivalence of highly variable drugs[J]. AAPS J,2008,10(3):450-454.
[12] LIU Y M,PU H H,LIU G Y,et al. Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets:a single-dose,randomized-sequences,open-label,two-period crossover study in healthy fasted Chinese adult males[J].Clin Ther,2010,32(7):1396-1407.
[13]沈懿,张逸凡,陈笑艳,等.阿托伐他汀在中国健康男性志愿者体内的药代动力学及生物等效性[J].中华心血管病杂志,2012,40(3):243-247.
[2] REBECCA G,BAKKER A,DAVIDSON MH,et al. Efficacy and safety of a new HMG-CoA reductase inhibitor,atorvastatin,in patients with hypertriglyceridemia[J]. JAMA,1996,275(2):128-133.
[3] PFIZER. LIPITOR(atorvastatin calcium)Tablets for Oral Administration[EB/OL]. Maryland:FDA,2018-08-10[2019-03-20]. https://www. accessdata. fda. gov/drugsatfda_docs/label/2018/020702s071lbl. pdf.
[4] YANG Y,XU Q,ZHOU L,et al. High-throughput salting-out-assisted liquid-liquid extraction for the simultaneous determination of atorvastatin, ortho-hydroxyatorvastatin, and parahydroxyatorvastatin in human plasma using ultrafast liquid chromatography with tandem mass spectrometry[J]. J Sep Sci,2015,38(6):1026-1034.
[5] OFFICE OF GENERIC DRUGS,FDA. Draft guidance for industry on bioequivalence recommmendations for progesterone capsules[EB/OL]. Maryland:FDA,2011-02-12[2018-04-12].https://www. fda. gov/downloads/Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM209294. pdf.
[6]刘东阳,李丽,江骥,等.高变异药物的生物等效性研究进展[J].中国临床药理学杂志,2008,24(4):339-343.
[7]刘曼,张丹,王晓琳,等.高变异药品及其参比制剂校正的平均生物等效性试验的探讨[J].中国新药杂志,2014,23(3):257-260.
[8]黄钦,魏春敏.浅谈高变异药物的生物等效性研究[J].中国临床药理学与治疗学,2007,12(8):841-844.
[9] HAIDAR S H,DAVIT B,CHEN M L,et al. Bioequivalence approaches for highly variable drugs and drug products[J]. Pharm Res,2008,25(1):237-241.
[10] EUROPEAN MEDICINES AGENCY(EMA). Committee for medicinal products for human use,CHMP. Guidance on the investigation of bioequivalence[EB/OL]. London:EMA,2010-08-01[2018-04-12]. http://www. ema. europa. eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039. pdf.
[11] HAIDAR S H,MAKHLOUF F,SCHUIRMANN D J,et al. Evaluation of a scaling approach for the bioequivalence of highly variable drugs[J]. AAPS J,2008,10(3):450-454.
[12] LIU Y M,PU H H,LIU G Y,et al. Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets:a single-dose,randomized-sequences,open-label,two-period crossover study in healthy fasted Chinese adult males[J].Clin Ther,2010,32(7):1396-1407.
[13]沈懿,张逸凡,陈笑艳,等.阿托伐他汀在中国健康男性志愿者体内的药代动力学及生物等效性[J].中华心血管病杂志,2012,40(3):243-247.