Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug dis...Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase III clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by establishing a physiologically based pharmacokinetics(PBPK)model.For in vitro–in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.展开更多
Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa.Maintaining a high local concentration of inhaled antibiotics for an extended t...Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa.Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency.In this study,we aim to investigate whether an extended exposure of ciprofloxacin(CIP),a model fluoroquinolone drug,in the lung epithelial lining fluid(ELF)could be achieved via a controlled-release formulation strategy.CIP solutions were intratracheally instilled to the rat lungs at 3 different rates,i.e.,T0h(fast),T2h(medium),and T4h(slow),to mimic different release profiles of inhaled CIP formulations in the lung.Subsequently,the concentration-time profiles of CIP in the plasma and the lung ELF were obtained,respectively,to determine topical exposure index(ELF-Plasma AUC Ratio,EPR).The in silico PBPK model,validated based on the in vivo data,was used to identify the key factors that influence the disposition of CIP in the plasma and lungs.The medium and slow rates groups exhibited much higher EPR than that fast instillation group.The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC.In contrast,the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC.The generated whole-body PBPK rat model,validated by comparison with the in vivo data,revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP.This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration.It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.展开更多
目的通过建立阿奇霉素的成人-儿童转化模型,为儿科临床用药提供指导性的建议,降低儿童用药风险,实现儿童临床个性化用药。方法查阅相关文献,利用成人的临床阿奇霉素口服给药试验的受试者生理参数结合阿奇霉素的药物特异参数,通过建立异...目的通过建立阿奇霉素的成人-儿童转化模型,为儿科临床用药提供指导性的建议,降低儿童用药风险,实现儿童临床个性化用药。方法查阅相关文献,利用成人的临床阿奇霉素口服给药试验的受试者生理参数结合阿奇霉素的药物特异参数,通过建立异速生长模型,生理药动学(physiologically based pharmacokinetic,PBPK)模型,根据文献提取的儿童个体口服阿奇霉素临床数据验证这2个模型的参数缩放公式的正确性。进一步利用这2种模型模拟出儿童相关药动学参数并计算出这些参数的相对偏差和相对标准误差。结果通过模拟发现2个模型得到的药动学参数cmax、tmax、AUC0-∞实测值接近,都在文献范围内,可认为2模型的参数转化公式正确。进一步计算参数的相对偏差和相对标准误差,成人-儿童PBPK预测模型的cmax、tmax、AUC0-∞的相对偏差和相对标准误差都比异速生长模型的小。结论阿奇霉素PBPK模型预测儿童药动学参数较异速生长模型要好。本研究所应用的口服用药成人-儿童模型特异性参数的缩放公式,经阿奇霉素验证成功,可以外推至其他药物,为其他口服给药的成人-儿童模型转化提供便利。展开更多
通过基于生理学的药动学(physiologically based pharmacokinetic,PBPK)建模策略预测晶型Ⅰ与晶型Ⅱ利福平在人体内的药动学行为,判断两者是否生物等效。对两种晶型利福平进行体外研究后,以大鼠静脉给药的药动学数据为基础,构建大鼠PBP...通过基于生理学的药动学(physiologically based pharmacokinetic,PBPK)建模策略预测晶型Ⅰ与晶型Ⅱ利福平在人体内的药动学行为,判断两者是否生物等效。对两种晶型利福平进行体外研究后,以大鼠静脉给药的药动学数据为基础,构建大鼠PBPK模型,再通过大鼠口服给药的药动学数据进行模型优化,种属外推至健康人体,利用外推模型预测两种晶型的利福平在健康人体内的血药浓度-时间曲线、吸收部位及吸收量等药动学行为。健康人体模型预测结果显示,晶型Ⅰ与晶型Ⅱ利福平的c_(max)分别为8.42和10.35μg/mL,t_(max)分别为0.40和0.32 h,AUC_(0-t)均为62.90μg·h/mL。根据吸收情况预测结果,晶型Ⅰ与晶型Ⅱ利福平在胃部均不被吸收,但在肠道被完全吸收,两者吸收部位及吸收量基本一致。晶型Ⅰ与晶型Ⅱ利福平的药动学参数十分接近,预测两者具有生物等效性。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
基金supported by the National Natural Science Foundation of China(Grant Nos.:82373938,82104275,and 82204585)Key Technologies R&D Program of Guangdong Province,China(Grant No.:2023B1111030004)National Key R&D Program of China(Grant No.:2022YFF1202600).
文摘Proteolysis-targeting chimeras(PROTACs)represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can,potentially revolutionizing drug discovery and treatment strategies.However,the links between in vitro and in vivo data are poorly understood,hindering a comprehensive understanding of the absorption,distribution,metabolism,and excretion(ADME)of PROTACs.In this work,14C-labeled vepdegestrant(ARV-471),which is currently in phase III clinical trials for breast cancer,was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics(PK)by establishing a physiologically based pharmacokinetics(PBPK)model.For in vitro–in vivo extrapolation(IVIVE),hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did.PBPK models,which were initially developed and validated in rats,accurately simulate ARV-471's PK across fed and fasted states,with parameters within 1.75-fold of the observed values.Human models,informed by in vitro ADME data,closely mirrored postoral dose plasma profiles at 30 mg.Furthermore,no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans.This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.
基金financially supported by the Liaoning Pan Deng Xue Zhe Scholar(No.XLYC2002061)the National Natural Science Foundation of China(No.81573380)+3 种基金the Overseas Expertise Introduction Project for Discipline Innovation(“111 Project”)(No.D20029)financial support from the Guiding Project for Science and Technology of Liaoning Province(No.2019-ZD-0448)Ministry of Education Chunhui Program(2020)support from Ministry of Education Science and Technological Development,Republic of Serbia(No.451-03-9/2021-14/200161)。
文摘Respiratory antibiotics have been proven clinically beneficial for the treatment of severe lung infections such as Pseudomonas aeruginosa.Maintaining a high local concentration of inhaled antibiotics for an extended time in the lung is crucial to ensure an adequate antimicrobial efficiency.In this study,we aim to investigate whether an extended exposure of ciprofloxacin(CIP),a model fluoroquinolone drug,in the lung epithelial lining fluid(ELF)could be achieved via a controlled-release formulation strategy.CIP solutions were intratracheally instilled to the rat lungs at 3 different rates,i.e.,T0h(fast),T2h(medium),and T4h(slow),to mimic different release profiles of inhaled CIP formulations in the lung.Subsequently,the concentration-time profiles of CIP in the plasma and the lung ELF were obtained,respectively,to determine topical exposure index(ELF-Plasma AUC Ratio,EPR).The in silico PBPK model,validated based on the in vivo data,was used to identify the key factors that influence the disposition of CIP in the plasma and lungs.The medium and slow rates groups exhibited much higher EPR than that fast instillation group.The ELF AUC of the medium and slow instillation groups were about 200 times higher than their plasma AUC.In contrast,the ELF AUC of the fast instillation group was only about 20 times higher than the plasma AUC.The generated whole-body PBPK rat model,validated by comparison with the in vivo data,revealed that drug pulmonary absorption rate was the key factor that determined pulmonary absorption of CIP.This study suggests that controlled CIP release from inhaled formulations may extend the exposure of CIP in the ELF post pulmonary administration.It also demonstrates that combining the proposed intratracheal installation model and in silico PBPK model is a useful approach to identify the key factors that influence the absorption and disposition of inhaled medicine.
文摘目的通过建立阿奇霉素的成人-儿童转化模型,为儿科临床用药提供指导性的建议,降低儿童用药风险,实现儿童临床个性化用药。方法查阅相关文献,利用成人的临床阿奇霉素口服给药试验的受试者生理参数结合阿奇霉素的药物特异参数,通过建立异速生长模型,生理药动学(physiologically based pharmacokinetic,PBPK)模型,根据文献提取的儿童个体口服阿奇霉素临床数据验证这2个模型的参数缩放公式的正确性。进一步利用这2种模型模拟出儿童相关药动学参数并计算出这些参数的相对偏差和相对标准误差。结果通过模拟发现2个模型得到的药动学参数cmax、tmax、AUC0-∞实测值接近,都在文献范围内,可认为2模型的参数转化公式正确。进一步计算参数的相对偏差和相对标准误差,成人-儿童PBPK预测模型的cmax、tmax、AUC0-∞的相对偏差和相对标准误差都比异速生长模型的小。结论阿奇霉素PBPK模型预测儿童药动学参数较异速生长模型要好。本研究所应用的口服用药成人-儿童模型特异性参数的缩放公式,经阿奇霉素验证成功,可以外推至其他药物,为其他口服给药的成人-儿童模型转化提供便利。
文摘通过基于生理学的药动学(physiologically based pharmacokinetic,PBPK)建模策略预测晶型Ⅰ与晶型Ⅱ利福平在人体内的药动学行为,判断两者是否生物等效。对两种晶型利福平进行体外研究后,以大鼠静脉给药的药动学数据为基础,构建大鼠PBPK模型,再通过大鼠口服给药的药动学数据进行模型优化,种属外推至健康人体,利用外推模型预测两种晶型的利福平在健康人体内的血药浓度-时间曲线、吸收部位及吸收量等药动学行为。健康人体模型预测结果显示,晶型Ⅰ与晶型Ⅱ利福平的c_(max)分别为8.42和10.35μg/mL,t_(max)分别为0.40和0.32 h,AUC_(0-t)均为62.90μg·h/mL。根据吸收情况预测结果,晶型Ⅰ与晶型Ⅱ利福平在胃部均不被吸收,但在肠道被完全吸收,两者吸收部位及吸收量基本一致。晶型Ⅰ与晶型Ⅱ利福平的药动学参数十分接近,预测两者具有生物等效性。
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.
