CYP3A4/5和MDR1基因多态性对西罗莫司药动学的影响

【作者】 钱李轩； 焦正；

【机构】 复旦大学附属华山医院药剂科；

【摘要】 目的:通过建立群体药动学模型,考察MDR1、CYP3A4*1G和CYP3A5*3的单核苷酸多态性（SNP）以及体重、剂型等因素对中国男性健康志愿者中西罗莫司药动学的影响。方法:收集整理3项中国男性健康志愿者单次口服西罗莫司的生物等效性试验中的药动学、人口统计学和基因学等数据。对3项研究中67例中国男性健康志愿者的1045个血药浓度数据进行分析。其中41例服用原研厂商生产的口服液,26例服用原研厂商生产的片剂。西罗莫司血药浓度的测定采用串联液相色谱-质谱法（LC-MS/MS）。采用群体药动学（PPK）方法对数据建模和分析,使用非线性混合效应模型法（NONMEM）中的个体间变异和残差变异有交互作用的一级条件算法（FOCE-I）进行群体药动学模型拟合。通过绘制拟合优度图（GOF）、直观预测检验（VPC）等方法对模型的可靠性、稳定性和预测能力进行评价。结果:模型的分布和消除过程采用经典的两房室模型。吸收相模型在一级吸收的基础上使用渐进模型（Transit Model）拟合并优化模型的吸收过程。上述结构模型可较好地模拟西罗莫司在体内的药动学过程。协变量筛选结果显示:体重对西罗莫司的清除率（CL/F）、中央室分布容积（V_C/F）、房室间清除率（Q/F）、周边室分布容积（V_P/F）有影响。剂型对生物利用度和吸收速率常数有影响。对各SNP的筛选显示CYP3A5*3对生物利用度有影响,但其最大影响程度的典型值仅为-11.2%,低于公认的具有临床意义的分界值±15%,故未在最终模型中纳入。此外,未见其他SNP对西罗莫司的药动学有显著影响。CL/F的典型值为14.5 L·h^-1,清除率的最终模型为:式中,WT为体重,单位为kg。GOF和VPC结果显示模型对于西罗莫司血药浓度的经时过程预测效果良好,具有较强的预测能力。讨论:过往的研究认为移植患者CYP3A5的基因多态性会影响西罗莫司的清除率。本研究中,我们发现在健康人中CYP3A5的基因多态性对生物利用度的影响更显著。鉴于CYP3A5亦在肠道内大量分布,我们认为该显现有合理的依据。但从单次给药的角度看该影响没有临床显著性。长期用药下CYP3A5的基因多态性是否能产生临床显著的影响仍待研究。更多还原

【Abstract】 To investigate the effects of ABCB1,CYP3 A4*1 G and CYP3 A5*3 genetic polymorphismson sirolimus PK in Chinese healthy subjects by population pharmacokinetics analysis.Methods:Data were collected from 3 comparative bioequivalencestudies using sirolimus solution or tablet in67 Chinese male volunteers with a single dose of 5 mg.The analysis was performed by Non-linear mixed effect modelling software(NONMEM).Exponential errors following a log-normal distribution were used for the description of the inter-individual variability of the parameters.The first-order conditional estimation with interaction method(FOCE-I) was used to estimate the population PK parameters.The stability and predictability of the final model was evaluated by goodness-of-fit(GOF),visual predictive check(VPC).Results:CYP3 A5*3 shows a limited effect on relative bioavailability(P <0.01) while its maximum effect(11.2%,*1/*3 &*3/*3) can barely change the dosages so that it is not involved in the final model.None of other genetic polymorphisms reach the significant line.With a bioavailability difference between solution and tablet(+28% for tablet) which is quite close to once reported(+28%～+30% for tablet),the inter-individual variability are mainly provided by body weight.Dosage forms have significant effects on absorption rate constant(Ka) and the transit progress since a transit model is introduced to improve the absorption phase.The relative plasma clearance is 14.5[13.453-15.547](mean[95% C.I.]) and fixed by body weight:CL/F=13.6·(WT/65)^0.75.The predictability of the final model was well tested by the visual predictive check and looks good.更多还原