The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dis...The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.展开更多
Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic...Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.展开更多
The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old m...The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.展开更多
苯并[α]芘[benzo[α]pyrene,BaP]是环境中广泛存在的一种致癌多环芳烃,带来的健康风险受到普遍关注.基于生理的药代动力学(physiologically based pharmacokinetic, PBPK)模型是一种预测污染物在生物体内部剂量的数学模型,近年来在健...苯并[α]芘[benzo[α]pyrene,BaP]是环境中广泛存在的一种致癌多环芳烃,带来的健康风险受到普遍关注.基于生理的药代动力学(physiologically based pharmacokinetic, PBPK)模型是一种预测污染物在生物体内部剂量的数学模型,近年来在健康风险评估中应用广泛.本文介绍了BaP对生物体的健康危害,概述了BaP的PBPK模型研究进展,指出了BaP人体PBPK模型存在BaP及代谢物的代谢机理尚未完全明确、代谢参数可靠性不高、模型还需继续完善等问题,并探讨了PBPK模型在BaP健康风险评估中的应用.一方面,PBPK模型在阐明内暴露监测结果及补充完善污染物在人体内的代谢机理方面具有明显优势,基于PBPK模型分析完善了BaP生物标志物3-羟基苯并[α]芘在肾小管重吸收的肾脏排泄机制;另一方面,PBPK模型作为外推工具,通过种间外推可以量化污染物的种间药代动力学差异,减小动物健康剂量水平外推至人体基准值的不确定性;通过体外到体内的外推可以关联内外暴露剂量,利用反剂量学推导人体健康基准值.这两种外推方法的应用均可以提高人体健康基准值推导的科学性、准确性.并以BaP为例剖析了PBPK模型不确定性来源,提出了提高模型精确性的方法.最后,为了进一步推动完善BaP的人体健康风险评估方法体系,本文探讨总结了3个重点研究方向:一是探索PBPK模型应用于BaP健康风险评估的方法体系;二是探索可靠性更高的Ba P健康风险评估概率模型;三是开展BaP的生物标志物用于人体健康风险评估可行性研究.展开更多
生理药动学(physiologically based pharmacokinetic,PBPK)模型是一种模拟药物在人或动物体内吸收、分布、代谢和排泄过程的数学模型,集成了药物的理化和系统(生理)信息,能描述药物在靶组织器官中的经时变化,用于药物研究的各个阶段。...生理药动学(physiologically based pharmacokinetic,PBPK)模型是一种模拟药物在人或动物体内吸收、分布、代谢和排泄过程的数学模型,集成了药物的理化和系统(生理)信息,能描述药物在靶组织器官中的经时变化,用于药物研究的各个阶段。本文将综述PBPK模型在抗感染药物研发及临床评价中的应用,为抗感染药物研发及临床合理应用提供参考。展开更多
The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscibl...The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.展开更多
基金the National Natural Science Foundation of China (No. 81173009)the Technology Bureau in Shenyang (No. ZCJJ2013402)the Project for New Century Excellent Talents of Ministry of Education (No. NCET-12-1015)
文摘The aim of the present study was to investigate virtual population pharmacokinetic using physiologically based pharmacokinetic(PBPK) model for evaluating bioequivalence of oral lacidipine formulations in dogs. The dissolution behaviors of three lacidipine formulations including one commercial product and two self-made amorphous solid dispersions(ASDs)capsules were determined in 0.07% Tween 80 media. A randomized 3-period crossover design in 6 healthy beagle dogs after oral administration of the three formulations at a single dose of 4 mg was conducted. The PBPK modeling was utilized for the virtual bioequivalence study.In vitro dissolution experiment showed that the dissolution behaviors of lacidipine amorphous solid dispersions(ASDs) capsules, which was respectively prepared by HPMC-E5 or Soluplus, as polymer displayed similar curves compared with the reference formulation in 0.07% Tween 80 media. In vivo pharmacokinetics experiments showed that three formulations had comparable maximum plasma drug concentration(Cmax), and the time(Tmax) to reach Cmax of lacidipine tablet, which was prepared by Soluplus, as polymer was slower than other two formulations in consistency with the in vitro dissolution rate. The 90% confidence interval(CI) for the Cmax, AUC0–24 h and AUC0–∞ of the ratio of the test drug to the reference drug exceeded the acceptable bioequivalence(BE) limits(0.80–1.25). However, the 90% CI of the AUC0–24 h, AUC0–∞ and Cmax of the ratio of test to reference drug were within the BE limit,calculated using PBPK modeling when the virtual subjects reached 24 dogs. The results all demonstrated that virtual bioequivalence study can overcome the inequivalence caused by inter-subject variability of the 6 beagle dogs involved in in vivo experiments.
基金supported by the National Natural Science Foundation of China (81473362)。
文摘Objective: To determine the in vitro and in vivo absorption properties of active ingredients of the Chinese medicine, baicalein, to enrich mechanistic understanding of oral drug absorption.Methods: The Biopharmaceutic Classification System(BCS) category was determined using equilibrium solubility, intrinsic dissolution rate, and intestinal permeability to evaluate intestinal absorption mechanisms of baicalein in rats in vitro. Physiologically based pharmacokinetic(PBPK) model commercial software GastroPlus~(TM) was used to predict oral absorption of baicalein in vivo.Results: Based on equilibrium solubility, intrinsic dissolution rate, and permeability values of main absorptive segments in the duodenum, jejunum, and ileum, baicalein was classified as a drug with low solubility and high permeability. Intestinal perfusion with venous sampling(IPVS) revealed that baicalein was extensively metabolized in the body, which corresponded to the low bioavailability predicted by the PBPK model. Further, the PBPK model predicted the key indicators of BCS, leading to reclassification as BCS-II. Predicted values of peak plasma concentration of the drug(C_(max)) and area under the curve(AUC)fell within two times of the error of the measured results, highlighting the superior prediction of absorption of baicalein in rats, beagles, and humans. The PBPK model supported in vitro and in vivo evidence and provided excellent prediction for this BCS class II drug.Conclusion: BCS and PBPK are complementary methods that enable comprehensive research of BCS parameters, intestinal absorption rate, metabolism, prediction of human absorption fraction and bioavailability, simulation of PK, and drug absorption in various intestinal segments across species. This combined approach may facilitate a more comprehensive and accurate analysis of the absorption characteristics of active ingredients of Chinese medicine from in vitro and in vivo perspectives.
文摘The safety and toxicity of chemicals given first to animals and finally to humans are generally estimated with a method of safe coefficient, which is scientifically a way lack of grounds. To make a change of the old method, we designed a Physiologically Based Pharmacokinetics Medel for the estimate of safety and toxicity of chemicais. As an example,p-nitrophenol sodium (PNP-Na) is used in the research work. Studies of the PNP-Na pharmacokinetics in bodies of rat as well as humans are made, and possibilities of making use of the Model in the estimate of safety and toxicity of chemicals are discussed.
文摘苯并[α]芘[benzo[α]pyrene,BaP]是环境中广泛存在的一种致癌多环芳烃,带来的健康风险受到普遍关注.基于生理的药代动力学(physiologically based pharmacokinetic, PBPK)模型是一种预测污染物在生物体内部剂量的数学模型,近年来在健康风险评估中应用广泛.本文介绍了BaP对生物体的健康危害,概述了BaP的PBPK模型研究进展,指出了BaP人体PBPK模型存在BaP及代谢物的代谢机理尚未完全明确、代谢参数可靠性不高、模型还需继续完善等问题,并探讨了PBPK模型在BaP健康风险评估中的应用.一方面,PBPK模型在阐明内暴露监测结果及补充完善污染物在人体内的代谢机理方面具有明显优势,基于PBPK模型分析完善了BaP生物标志物3-羟基苯并[α]芘在肾小管重吸收的肾脏排泄机制;另一方面,PBPK模型作为外推工具,通过种间外推可以量化污染物的种间药代动力学差异,减小动物健康剂量水平外推至人体基准值的不确定性;通过体外到体内的外推可以关联内外暴露剂量,利用反剂量学推导人体健康基准值.这两种外推方法的应用均可以提高人体健康基准值推导的科学性、准确性.并以BaP为例剖析了PBPK模型不确定性来源,提出了提高模型精确性的方法.最后,为了进一步推动完善BaP的人体健康风险评估方法体系,本文探讨总结了3个重点研究方向:一是探索PBPK模型应用于BaP健康风险评估的方法体系;二是探索可靠性更高的Ba P健康风险评估概率模型;三是开展BaP的生物标志物用于人体健康风险评估可行性研究.
文摘生理药动学(physiologically based pharmacokinetic,PBPK)模型是一种模拟药物在人或动物体内吸收、分布、代谢和排泄过程的数学模型,集成了药物的理化和系统(生理)信息,能描述药物在靶组织器官中的经时变化,用于药物研究的各个阶段。本文将综述PBPK模型在抗感染药物研发及临床评价中的应用,为抗感染药物研发及临床合理应用提供参考。
文摘The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.
