应用生理药动学模型评估雷尼替丁片剂生物等效豁免的影响因素

Application of physiologically based pharmacokinetic models to evaluate the factors affecting the biowaiver of ranitidine tablets

目的:建立雷尼替丁片剂在健康人体内的生理药动学(PBPK)模型,并用该模型模拟各因素对盐酸雷尼替丁片剂生物等效性的影响,为生物等效豁免标准的制定提供参考。方法:查询不同数据库关于雷尼替丁理化参数的相关文献,遵照美国食品与药物监督管理局(FDA)的生物等效研究的指导原则,采用GastroPlus^(TM)9.5软件建立雷尼替丁注射给药和口服给药的PBPK模型,并通过倍数误差来评价模型的有效性;再根据已建立的PBPK模型对可能影响雷尼替丁片剂生物等效性的各因素进行体内模拟。结果:PBPK模型预测雷尼替丁的药-时曲线与实测值拟合良好。药动学参数最大血药浓度(C_(max))、达峰时间(t_(max))、血药浓度-时间曲线下总面积(AUC_(0-inf))和截止至终末观察点时的血浆药物浓度-时间曲线下面积(AUC_(0-t))与实测值接近,倍数误差<2。影响因素沉淀时间(90～9 000 s)、胃pH(0.5～6)、十二指肠pH(0.5～8)、溶解度(100～10 000 g·L^(-1))对C_(max)和AUC_(0-t)值几乎无影响;当胃排空时间在0.125～0.5 h内时,随着胃排空时间延长,C_(max)略有下降,AUC_(0-t)基本不变,C_(max)和AUC_(0-t)均符合生物等效(BE)标准;当渗透性在(0.62～2.48)×10^(-4 )cm·s^(-1)内时,随着渗透性增加,C_(max)和AUC_(0-t)均增加;C_(max)在渗透性为(0.84～1.82×10^(-4 ))cm·s^(-1)时符合BE标准,在渗透性研究范围之内AUC_(0-t)均符合BE标准;当小肠转运时间在1.586～6.344 h内时,随着小肠转运时间增加,C_(max)略有增加,AUC_(0-t)也略有增加,C_(max)和AUC_(0-t)都符合BE标准;在120 min内药物溶出度达到85%时,不同制剂与口服溶液在体内的C_(max)和AUC_(0-t)是一致的,不会受溶出的影响。结论:所建PBPK模型准确可靠,可用于模拟和评价各因素对BE试验的影响程度,为生物等效豁免标准的制定提供参考。

OBJECTIVE To establish a physiological pharmacokinetics(PBPK)model of ranitidine tablets in healthy volunteers,and to simulate the effects of various factors on the bioequivalence of ranitidine hydrochloride tablets,so as to provides a reference for the formulation of the equivalent exemption standard.METHODS Different databases were searched for relevant literatures on the physical and chemical parameters of ranitidine.According to the guidelines for bioequivalence study of the US Food and Drug Administration(FDA),the PBPK model of ranitidine for injection and oral administration was established using GastroPlusTM 9.5 software,and the validity of the model was evaluated by the fold error.Then,the factors which may affect the bioequivalence of ranitidine tablets were simulated in vivo according to the established PBPK model.RESULTS The PBPK model predicted that the drug-time curve of ranitidine fit well with the measured values.Pharmacokinetic parameters:maximum blood concentration(Cmax),peak time(tmax),total area under the blood concentration-time curve(AUC0-inf),and area under the plasma drug concentration-time curve at the end of the observation point(AUC0-t)was close to the measured value,and the multiple error is<2.Influencing factors including precipitation time(between 90-9 000 s),gastric pH(between 0.5 and 6),duodenal pH(between 0.5 and 8),solubility(at 100 to 10 000 g·L-1)showed almost no effect on the Cmax and AUC0-t values;when the gastric emptying time is within 0.125-0.5 h,Cmax decreases slightly as the gastric emptying time increases while AUC0-t remains basically unchanged,and Cmax along with AUC0-t was consistent with the bioequivalence(BE)standard;when the permeability is within(0.62-2.48)×10-4 cm·s-1,both Cmax and AUC0-t increase with the rise of permeability;Cmax in permeability of(0.84-1.82)×10-4 cm·s-1 meets the BE standard,and AUC0-t meets the BE standard within the permeability study range;when the small intestinal transit time is within 1.586-6.344 h,the intestinal transit time increases.Both Cmax and AUC0-t increased slightly,Cmax and AUC0-t were in accordance with BE standard;when the drug dissolution reached 85%in 120 min,the Cmax and AUC0-t of different preparations and oral solution in vivo were consistent,and not be affected by dissolution.CONCLUSION The established PBPK model is accurate and reliable,and can be used to simulate and evaluate the influence of various factors on the BE test,thus providing reference for the formulation of the bioequivalent exemption standard.