Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic ...Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment.PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and development.In this mini-review,the concept and methodology of PBPK modeling are briefly introduced.Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development.These case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical trials.The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.展开更多
Chloroquine(CQ)phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019(COVID-19).To develop a physiologically-based pharmacokinetic(PBPK)model for predicting tissue distrib...Chloroquine(CQ)phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019(COVID-19).To develop a physiologically-based pharmacokinetic(PBPK)model for predicting tissue distribution of CQ and apply it to optimize dosage regimens,a PBPK model,with parameterization of drug distribution extrapolated from animal data,was developed to predict human tissue distribution of CQ.The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism.Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships.The model was also validated by clinical data from Chinese patients with COVID-19.The novel PBPK model allows indepth description of the pharmacokinetics of CQ in several key organs(lung,heart,liver,and kidney),and was applied to design dosing strategies in patients with acute COVID-19(Day 1:750 mg BID,Days 2-5:500 mg BID,CQ phosphate),patients with moderate COVID-19(Day 1:750 mg and 500 mg,Days 2-3:500 mg BID,Days 4-5:250 mg BID,CQ phosphate),and other vulnerable populations(e.g.,renal and hepatic impairment and elderly patients,Days 1-5:250 mg BID,CQ phosphate).A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.展开更多
Background:Secondary antimicrobial resistance bacterial(AMR)pneumonia could lead to an increase in mortality in COVID-19 patients,particularly of geriatric patients with underlying diseases.The comedication of current...Background:Secondary antimicrobial resistance bacterial(AMR)pneumonia could lead to an increase in mortality in COVID-19 patients,particularly of geriatric patients with underlying diseases.The comedication of current medicines for AMR pneumonia with corticosteroids may lead to suboptimal treatment or toxicities due to drug-drug interactions(DDIs).Objective:This study aimed to propose new promising dosage regimens of photoactivated curcumin when co-administered with corticosteroids for the treatment of antimicrobial resistance(AMR)pneumonia in COVID-19 patients.Methods:A whole-body physiologically-based pharmacokinetic(PBPK)with the simplified lung compartments model was built and verified following standard model verification(absolute average-folding error or AAFEs).The pharmacokinetic properties of photo-activated were assumed to be similar to curcumin due to minor changes in physiochemical properties of compound by photoactivation.The acceptable AAFEs values were within 2-fold.The verified model was used to simulate new regimens for different formulations of photoactivated curcumin.Results:The AAFEs was 1.12-fold.Original formulation(120 mg once-daily dose)or new intramuscular nano-formulation(100 mg with a release rate of 10/h given every 7 days)is suitable for outpatients with MRSA pneumonia to improve patient adherence.New intravenous formulation(2000 mg twice-daily doses)is for hospitalized patients with both MRSA and VRSA pneumonia.Conclusion:The PBPK models,in conjunction with MIC and applied physiological changes in COVID-19 patients,is a potential tool to predict optimal dosage regimens of photo-activated curcumin for the treatment of co-infected AMR pneumonia in COVID-19 patients.Each formulation is appropriate for different patient conditions and pathogens.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
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
多柔比星(doxorubicin,DOX)在临床广泛应用于实体肿瘤、淋巴瘤和白血病等的治疗。DOX的细胞毒性作用和心脏毒性作用,使得其在发挥抗肿瘤作用的同时也产生严重毒副作用,限制了临床应用。这促使研究者不断深入了解其体内药动学、作用机制...多柔比星(doxorubicin,DOX)在临床广泛应用于实体肿瘤、淋巴瘤和白血病等的治疗。DOX的细胞毒性作用和心脏毒性作用,使得其在发挥抗肿瘤作用的同时也产生严重毒副作用,限制了临床应用。这促使研究者不断深入了解其体内药动学、作用机制,找到适宜的临床治疗方案,以及开发出新的制剂或给药系统。在DOX的研究过程中,基于生理的药物动力学模型(physiologically based pharmacokinetic model,PBPK)发挥了非常重要的作用。本文从DOX的PBPK模型发展到应用于DOX给药方案设计、药动学影响因素分析、细胞毒性和心脏毒性作用机制以及指导DOX前药及新制剂开发研究等方面进行介绍,对DOX的PBPK模型发展及其应用进展进行了概述。展开更多
In the development of new drugs as well as new formulations of existing products(including generic products),it is of great interest to be able to predict to what extent the drug can be absorbed from the gastrointesti...In the development of new drugs as well as new formulations of existing products(including generic products),it is of great interest to be able to predict to what extent the drug can be absorbed from the gastrointestinal(GI)tract and how the formulation and dosing conditions may affect the absorption profile.The hypothesis behind Biorelevant release testing is that“the closer the test conditions can simulate the gastrointestinal environment,the better the prediction will be.”Typical aspects of GI physiology,which can influence drug bioavailability,are the composition of the GI fluids(which affects various processes including release from the dosage form and stability of the drug),GI motility and hydrodynamics(transit characteristics of the dosage form,release from the dosage form etc.).展开更多
文摘Physiologically based pharmacokinetic(PBPK) modeling and simulation can be used to predict the pharmacokinetic behavior of drugs in humans using preclinical data.It can also explore the effects of various physiologic parameters such as age,ethnicity,or disease status on human pharmacokinetics,as well as guide dose and dose regiment selection and aid drug–drug interaction risk assessment.PBPK modeling has developed rapidly in the last decade within both the field of academia and the pharmaceutical industry,and has become an integral tool in drug discovery and development.In this mini-review,the concept and methodology of PBPK modeling are briefly introduced.Several case studies were discussed on how PBPK modeling and simulation can be utilized through various stages of drug discovery and development.These case studies are from our own work and the literature for better understanding of the absorption,distribution,metabolism and excretion(ADME) of a drug candidate,and the applications to increase efficiency,reduce the need for animal studies,and perhaps to replace clinical trials.The regulatory acceptance and industrial practices around PBPK modeling and simulation is also discussed.
基金supported by the“13th Five-Year”National Science and Technology Major Project(grant Nos.2017ZX09101001-002-001 and 2017ZX09304012,China)Bill&Melinda Gates Foundation(OPP1204780,USA)
文摘Chloroquine(CQ)phosphate has been suggested to be clinically effective in the treatment of coronavirus disease 2019(COVID-19).To develop a physiologically-based pharmacokinetic(PBPK)model for predicting tissue distribution of CQ and apply it to optimize dosage regimens,a PBPK model,with parameterization of drug distribution extrapolated from animal data,was developed to predict human tissue distribution of CQ.The physiological characteristics of time-dependent accumulation was mimicked through an active transport mechanism.Several dosing regimens were proposed based on PBPK simulation combined with known clinical exposure-response relationships.The model was also validated by clinical data from Chinese patients with COVID-19.The novel PBPK model allows indepth description of the pharmacokinetics of CQ in several key organs(lung,heart,liver,and kidney),and was applied to design dosing strategies in patients with acute COVID-19(Day 1:750 mg BID,Days 2-5:500 mg BID,CQ phosphate),patients with moderate COVID-19(Day 1:750 mg and 500 mg,Days 2-3:500 mg BID,Days 4-5:250 mg BID,CQ phosphate),and other vulnerable populations(e.g.,renal and hepatic impairment and elderly patients,Days 1-5:250 mg BID,CQ phosphate).A PBPK model of CQ was successfully developed to optimize dosage regimens for patients with COVID-19.
基金supported by postdoctoral fellowship,Thammasat University(Rangsit Campus),ThailandKesara Na-Bangchang was received funding from Thammasat University under the project Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma(No.1/2556,dated October 12,2013)+1 种基金the National Research Council of Thailand(No.45/2561,dated September 10,2018)Kesara Na-Bangchang is supported by the National Research Council of Thailand under the Research Team Promotion grant(grant number NRCT 820/2563,dated November 12,2020).
文摘Background:Secondary antimicrobial resistance bacterial(AMR)pneumonia could lead to an increase in mortality in COVID-19 patients,particularly of geriatric patients with underlying diseases.The comedication of current medicines for AMR pneumonia with corticosteroids may lead to suboptimal treatment or toxicities due to drug-drug interactions(DDIs).Objective:This study aimed to propose new promising dosage regimens of photoactivated curcumin when co-administered with corticosteroids for the treatment of antimicrobial resistance(AMR)pneumonia in COVID-19 patients.Methods:A whole-body physiologically-based pharmacokinetic(PBPK)with the simplified lung compartments model was built and verified following standard model verification(absolute average-folding error or AAFEs).The pharmacokinetic properties of photo-activated were assumed to be similar to curcumin due to minor changes in physiochemical properties of compound by photoactivation.The acceptable AAFEs values were within 2-fold.The verified model was used to simulate new regimens for different formulations of photoactivated curcumin.Results:The AAFEs was 1.12-fold.Original formulation(120 mg once-daily dose)or new intramuscular nano-formulation(100 mg with a release rate of 10/h given every 7 days)is suitable for outpatients with MRSA pneumonia to improve patient adherence.New intravenous formulation(2000 mg twice-daily doses)is for hospitalized patients with both MRSA and VRSA pneumonia.Conclusion:The PBPK models,in conjunction with MIC and applied physiological changes in COVID-19 patients,is a potential tool to predict optimal dosage regimens of photo-activated curcumin for the treatment of co-infected AMR pneumonia in COVID-19 patients.Each formulation is appropriate for different patient conditions and pathogens.
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.
文摘多柔比星(doxorubicin,DOX)在临床广泛应用于实体肿瘤、淋巴瘤和白血病等的治疗。DOX的细胞毒性作用和心脏毒性作用,使得其在发挥抗肿瘤作用的同时也产生严重毒副作用,限制了临床应用。这促使研究者不断深入了解其体内药动学、作用机制,找到适宜的临床治疗方案,以及开发出新的制剂或给药系统。在DOX的研究过程中,基于生理的药物动力学模型(physiologically based pharmacokinetic model,PBPK)发挥了非常重要的作用。本文从DOX的PBPK模型发展到应用于DOX给药方案设计、药动学影响因素分析、细胞毒性和心脏毒性作用机制以及指导DOX前药及新制剂开发研究等方面进行介绍,对DOX的PBPK模型发展及其应用进展进行了概述。
文摘In the development of new drugs as well as new formulations of existing products(including generic products),it is of great interest to be able to predict to what extent the drug can be absorbed from the gastrointestinal(GI)tract and how the formulation and dosing conditions may affect the absorption profile.The hypothesis behind Biorelevant release testing is that“the closer the test conditions can simulate the gastrointestinal environment,the better the prediction will be.”Typical aspects of GI physiology,which can influence drug bioavailability,are the composition of the GI fluids(which affects various processes including release from the dosage form and stability of the drug),GI motility and hydrodynamics(transit characteristics of the dosage form,release from the dosage form etc.).
