复方孕二烯酮片剂和贴片在中国健康受试者中的群体药代动力学研究  

Population pharmacokinetics of combined ethinylestradiol/gestodene transdermal contraceptive tablets and patches in Chinese healthy volunteers

作　　者：刘洋[1,2] 张弨[1] 翟所迪[1] LIU Yang1＇2,ZHANG Chao ,ZHAI Suo - di(l. Department of Pharmacy, Peking University Third Hospital, Belling, 100191, China ; 2. Department of Pharnutcy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, Chin)

机构地区：[1]北京大学第三医院药剂科,北京100191 [2]北京大学药学院药事管理与临床药学系,北京100191

出　　处：《中国临床药理学杂志》2018年第7期870-874,880,共6页The Chinese Journal of Clinical Pharmacology

摘　　要：目的评价复方孕二烯酮片剂和贴片在中国健康受试者中的群体药代动力学(PPK)特征。方法 12名健康女性受试者按照开放、平行、两周期对照研究的试验设计,分别先后给予单剂量复方孕二烯酮片剂和复方孕二烯酮贴片,血样采集后使用高效液相色谱串联质谱法测定血浆中孕二烯酮(GSD)和炔雌醇(EE)浓度,并用非线性混合效应模型(NONMEM)法对试验数据进行处理,获得群体药代动力学参数。结果复方孕二烯酮片剂中GSD和EE体内药代动力学过程均符合一级吸收和消除的二室模型,而在贴片剂型中,建模结果显示GSD应采用零级吸收、一级消除的一室模型拟合,EE则使用一级吸收和消除的一室模型拟合更为适宜。研究中未发现对片剂和贴片中GSD和EE药代动力学参数具有显著影响的协变量。结论本模型稳定性较好,能较好地描述复方孕二烯酮片剂和贴片在中国健康受试者中的药代动力学特征。Objective To evaluate the population pharmacokinetics （PPK） of combined gestodene （GSD） / ethinylestradiol （EE） oral tablet and transdermal contraceptive patch in Chinese healthy volunteers, and provide theoretic supports for personalized medication. Methods An open - label, two - period comparative study was conducted in 12 healthy women volunteers. A single dose of combined GSD/EE oral tablet and transdermal contraceptive patch were administered. Blood samples at different time points after dose were collected, and concentrations were analyzed. A reliable, highly sensitive and accurate high -performance liquid chromatography coupled with tandem mass spectrometry assay method was developed in this study to determine the plasma concentra- tions of GSD and EE. The population pharmacokinetic parameters were estimated by nonlinear mixed effect model （NONMEM）. Results A two -compartment model with first -order absorption and first -order elimi- nation process was built as the structural model for GSD and EE of the tablet, respectively. Meanwhile, a one -compartment model with zero - order input and first - order elimination best described the GSD plasma concentrations after a single dose administration of the patch, and a one -compartment model with first- order absorption and first -order elimination for EE of the patch adequately described the data. Whencovariates were tested, none were found to adequately explain the changes of GSD and EE pharmacokinetic parameters in the PPK model for each route. Conclusion The established PPK models are capable of depicting pharmacokinetics of combined GSD/EE oral tablet and transdermal contraceptive patch in Chinese healthy volunteers. The final models are stable, and further research is warranted to study the effect of the potential covariates on GSD and EE pharmacoki- netic parameters to improve the predictive performance.

关 键 词：孕二烯酮 炔雌醇 群体药代动力学 经皮给药避孕贴片 

分 类 号：R977.1[医药卫生—药品]