洛匹那韦利托那韦片在中国健康志愿者中的生物等效性和安全性研究  

Bioequivalence and safety of lopinavir-ritonavir tablets in healthy Chinese subjects

作　　者：刘天美 杜晓琳 雍小兰 LIU Tian-mei;DU Xiao-lin;YONG Xiao-lan(Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College,Chengdu 610055,China)

机构地区：[1]川北医学院附属成都新华医院,成都610055

出　　处：《中国新药杂志》2024年第20期2143-2148,共6页Chinese Journal of New Drugs

摘　　要：目的:评价国产洛匹那韦利托那韦片(受试制剂)和进口洛匹那韦利托那韦片(参比制剂)在受试者空腹条件下的生物等效性和安全性。方法:采用单中心随机开放二序列交叉设计,受试者空腹口服洛匹那韦利托那韦受试制剂或参比制剂400 mg/100 mg,采用高效液相色谱-串联质谱法(high-performance liquid chromatography-tandem mass spectrometry,HPLC-MS/MS)测定人血浆中药物浓度。使用Phoenix WinNonlin 8.3.3软件计算主要药动学参数,并评价生物等效性。结果:受试制剂和参比制剂的洛匹那韦药动学参数C_(max),AUC_(0~t)和AUC_(0~∞)几何均数的比值及其90%置信区间分别为104.58%(101.24%,108.03%),104.77%(100.08%,109.69%),104.94%(100.54%,109.53%),置信区间落在等效性界值(80%,125%)之间。参比制剂中利托那韦的C_(max),AUC_(0~t)和AUC_(0~∞)的个体内标准差(subject within-subject repeatability,SWR)分别为0.2813,0.2294和0.2258,均<0.294(即个体内CV%<30%),则采用平均生物等效性方法(average bioequivalence,ABE)对其进行评价。受试制剂和参比制剂的利托那韦药动学参数C_(max),AUC_(0~t)和AUC_(0~∞)几何均数的比值及其90%置信区间分别为105.79%(99.12%,112.91%),104.03%(98.75%,109.58%),103.62%(98.50%,109.01%),置信区间落在等效性界值(80%,125%)之间。结论:受试制剂和参比制剂中洛匹那韦及利托那韦的C_(max),AUC_(0~t)和AUC_(0~∞)在受试者空腹状态下生物等效性成立,且安全性与耐受性较好。Objective:To evaluate the bioequivalence and safety of domestic(test)and imported lopinavir-ritonavir tablets(reference)under fasting condition.Methods:A single-center,randomized,open,two-sequence,cross-over design was used.The concentrations of lopinavir-ritonavir or reference preparation 400 mg/100 mg in human plasma were determined by high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).The main pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.3.3 and the bioequivalence were evaluated.Results:The geometric mean ratios(90%confidence intervals)of C_(max),AUC_(0~t)and AUC_(0~∞)of lopinavir of test preparation and reference preparation were 104.58%(101.24%,108.03%),104.77%(100.08%,109.69%),and 104.94%(100.54%,109.53%),respectively,and the confidence intervals fell between the equivalence threshold(80%~125%).The SWR of C_(max),AUC_(0~t)and AUC_(0~∞)of ritonavir in reference preparation were 0.2813,0.2294 and 0.2258,respectively,all were less than 0.294(intra-individual CV%<30%),so the mean bioequivalence method(ABE)was used to evaluate ritonavir.The geometric mean ratios(90%confidence intervals)of C_(max),AUC_(0~t)and AUC_(0~∞)of ritonavir of the test preparation and the reference preparation were 105.79%(99.12%,112.91%),104.03%(98.75%,109.58%),and 103.62%(98.50%,109.01%),respectively,and the confidence intervals fell between the equivalence threshold(80%~125%).Conclusion:The bioequivalence of the C_(max),AUC_(0~t)and AUC_(0~∞)of lopinavir and ritonavir in test and reference preparations are valid in fasting state,and the safety and tolerability are good.

关 键 词：洛匹那韦利托那韦 中国健康受试者 空腹 药动学 生物等效性 

分 类 号：R969.4[医药卫生—药理学]