摘要
目的:建立头孢地尼在健康人体内的生理药动学(PBPK)模型,预测其口服后在人体内的药动学过程。方法:以"头孢地尼""cefdinir""log P""p Ka"等为关键词,检索中国知网、Science Direct和Pub Med等数据库关于头孢地尼理化常数的相关文献,遵照美国食品与药物管理局的相关指导原则和前期临床试验方案,采用Gastro PlusTM8.6软件建立头孢地尼口服给药的PBPK模型,并通过倍数误差来评价模型的有效性;运用该PBPK模型模拟头孢地尼在胃肠道吸收情况;以头孢地尼参比制剂(颗粒剂和胶囊剂)释放速率t85%=15 min(即累积溶出85%的时间为15 min)时的c_(max)和AUC_(0-∞)为参比,通过单次和群体(n=500)模拟试验,评价受试制剂与参比制剂的生物等效性。结果:PBPK模型预测头孢地尼的药-时曲线与实测值拟合良好,R^2≥0.95;药动学参数c_(max)、t_(max)、AUC_(0-∞)与实测值接近,倍数误差<2。口服给药后,头孢地尼主要在肠道吸收(45.6%),主要吸收部位为空肠1段(14.8%);其吸收量明显低于吸收部位的释放量,4 h左右达到最大吸收分数(约40%)。单次模拟试验结果显示,受试制剂与参比制剂的c_(max)和AUC_(0-∞)比较,差异均无统计学意义(P>0.05);群体模拟试验结果显示,受试颗粒和受试胶囊的相对生物利用度分别为99.01%~102.99%、97.60%~105.90%,其cmax和AUC_(0-∞)的90%置信区间均在参比制剂相应参数的80%~125%之内。结论:该PBPK模型准确可靠,可为头孢地尼制剂的药动学研究和生物等效性评价提供参考。受试制剂与参比制剂生物等效。
OBJECTIVE：To establish physiological pharmacokinetic （PBPK） model of cefdinir in healthy volunteers,and to predict pharmacokinetic process of cefdinir in volunteers after oral administration. METHODS：Using“toubao dini”“cefdinir”“logP”“pKa”as keywords,related literatures about physico-chemical constants of cefdinir were retrieved from CNKI,ScienceDi-rect,PubMed and other databases;according to related guidelines and preliminary clinical trial plan of FDA,GastroPlusTM 8.6 soft-ware was used to establish PBPK model of oral administration of cefdinir;the effectiveness of the model was evaluated by multiple error. The model was used to simulate the absorption of cefdinir in the gastrointestinal tracts. The bioequivalence of test preparation and reference preparation were evaluated through single and population（n=500）simulation tests using cmax and AUC0-∞ of cefdinir reference preparation （capsule and granular formulation） as factors when release rate t85%=15 min （i.e. accumulatively released 85% within 15 min）. RESULTS：The blood concentration-time curves of cefdinir predicted by PBPK model fitted well with mea-sured value（R2≥0.95）;the pharmacokinetic parameters（cmax,tmax,AUC0-∞）were close to measured results,and the multiple er-rors were less than 2. After oral administration,cefdinir was mainly absorbed by the intestinal tract （45.6%）,especially by seg-ment 1 of jejunum（14.8%）;the absorption amount was significantly lower than the release amount of absorption site,and reached the maximal value（about 40%）within 4 h. The results of single simulation test showed that there was no statistical significance in cmax and AUC0-∞ between cefdinir test and reference preparations （P〉0.05）. The results of population simulation test showed that the relative bioavailability of cefdinir test particle and test capsule respectively were 99.01%-102.99% and 97.60%-105.90%;90%CI of cmax and AUC0-∞ values were within 80%-125% of reference preparation. CONCLUSIONS：The PBPK model is accurate and reliable in this study,can provide reference for pharmacokinetic study and bioequivalence evaluation of cefdinir preparations. Test preparation and reference preparation are equivalent.
出处
《中国药房》
CAS
北大核心
2016年第35期4920-4923,共4页
China Pharmacy
基金
国家自然科学基金资助项目(No.81473287)
