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@#Virtual clinical trials are clinical trials conducted through computer simulation technology, which breaks through the limitations of traditional clinical trials and has the advantages of saving time, reducing costs, and reducing the risk of human trials. With the application of new computer technologies such as population pharmacokinetics, physiologically-based pharmacokinetics, quantitative systems pharmacology, and artificial intelligence, the field of virtual clinical trials in healthcare has become an important development direction. This article will give a preliminary review of the connotation, methods and future development trends of virtual clinical trials, aiming to provide reference for the application of new technologies and methods in clinical trials.
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Quantitative systems pharmacology (QSP) modeling is an emerging computational medicine approach with growing applications and significance in modern drug development. QSP models are generally formulated based on multiscale disease mechanisms and drug-target interactions, which makes them capable of integrating multimodal data from the preclinical and clinical space. This also enables them to generate quantitative characterization of the dynamic disease progression as well as high-throughput predictions of drug-induced efficacy and toxicity signals. Therefore, QSP modeling and model-based virtual clinical trials have been widely implemented to guide drug development, in scenarios such as target identification and assessment, clinical trial design, evaluation of combination therapy and biomarkers, and personalized medicine. In US and Europe, QSP modeling has been developing rapidly in the past 10 years and is now an integral part of the model-informed drug development paradigm; however, in China it is still a nascent field. Here we will present a comprehensive review of the recent advancements of QSP and its impact in modern drug development through a number of case studies. This review will provide guidance for the future drug development efforts and the growth of QSP practice in China.
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In the context of Pharma 4.0, the design tools that support the pharmaceutical Quality by Design(QbD) are iterating fast toward intelligent or smart design. The conventional development methods for traditional Chinese medicine(TCM) preparations have the limitations such as over dependence on experience, low dimensions for the designed experiment parameters, poor compatibility between the process and equipment, and high trial-and-error cost during process scale-up. Therefore, this paper innovatively proposed the intelligent co-design involving material, process, and equipment for manufacturing high-quality TCM preparations, and introduced the design philosophy, targets, tools, and applications with TCM oral solid dosage(OSD) as an example. In terms of design philosophy, the pharmaceutical design tetrahedron composed of critical material attributes, critical process parameters, critical equipment attributes, and critical quality attributes was developed. The design targets were put forward based on the product performance classification system. The design tools involve a design platform that contains several modules, such a as the iTCM material database, the processing route classification system, the system modeling and simulation, and reliability-based optimization. The roles of different modules in obtaining essential and universal design knowledge of the key common manufacturing units were introduced. At last, the applications of the co-design methodology involving material, process, and equipment in the high shear wet granulation process development and the improvement of the dissolving or dispersion capability of TCM formula granules are illustrated. The research on advanced pharmaceutical design theory and methodology will help enhance the efficiency and reliability of drug development, improve the product quality, and promote the innovation of high-end TCM products across the industry.
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Medicine, Chinese Traditional , Reproducibility of Results , Quality Control , Computer Simulation , Commerce , Pharmaceutical Preparations , Drugs, Chinese HerbalABSTRACT
The rational medication in pregnant women is a clinical issue that clinicians and pharmacists must take seriously. Most tissues and organs undergo anatomical and physiological changes during pregnancy that affect the absorption, distribution, metabolism, and excretion of drugs in vivo, which ultimately lead to changes in bioavailability. In order to achieve an effective therapeutic concentration, dose adjustment might be required during this period. In the past ten years, the application of modeling and simulation methods in the field of drug development and clinical therapy has continued to expand, for instance, using population pharmacokinetic (PPK) and physiologically based pharmacokinetic (PBPK) modeling to adjust dosage regimen in special populations. Rigorously designed and validated models will effectively make up for the deficiencies of clinical trials, provide valuable references for the design of clinical research, and even replace part of them. This article will introduce the physiological changes that affect the pharmacokinetic properties of the drug during pregnancy and review the progress in the application of PBPK modeling in pharmacokinetic studies in pregnant women.
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Model informed precision dosing for warfarin is to provide individualized dosing by integrating information related to patient characteristics, disease status and pharmacokinetics /pharmacodynamics of warfarin, through mathematical modeling and simulation techniques based on the quantitative pharmacology. Compared with empirical dosing, it can improve the safety, effectiveness, economy, and adherence of pharmacotherapy of warfarin. This consensus report describes the commonly used modeling and simulation techniques for warfarin, their application in developing and adjusting dosing regimens, medication adherence and economy. Moreover, this consensus also elaborates the detailed procedures for the implementation in the warfarin pharmacy service pathway to facilitate the development and application of model informed precision dosing for warfarin.
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Abstract Natural gas steam reforming is commonly used for hydrogen production. However, research has shown that ethanol autothermal reforming can produce cleaner hydrogen gas efficiently. Despite this, there is a lack of studies on the energy self-sufficiency conditions of the ethanol autothermal reform. In this paper, we use simulations and the Response Surface Methodology (RSM) for the multivariate analysis of the energy self-sufficiency conditions in this process. First, we constructed and validated an industrial flowchart. After that, RSM allowed us to assess the process variables effects. The process variables studied were temperature (0 to 1000 ºC), pressure (20 to 30 bar), steam/ethanol ratio (2 to 5 mol/mol) and O2/ethanol ratio (0 to 1.5 mol/mol). We observe that the temperature and steam/ethanol ratio increase have a positive effect on hydrogen production. On the contrary, the O2/ethanol ratio increase has a negative effect, and the pressure increase is not statistically significant on hydrogen production. Therefore, the pressure was used at its minimum level (20 bar) while the temperature and the steam/ethanol ratio at its maximum levels (1000 ºC and 5 mol/mol). We also evaluated the energy consumption for the Autothermal Reactor (ATR). The reactor consumed 477.92 kJ/mol ethanol to produce 5.12 mol H2/mol ethanol when we use 1000 ºC, 20 bar, steam/ethanol 5 mol/mol, and O2/ethanol 0 mol/mol. ATR's energy self-sufficiency is achieved by using 1000 ºC, 20 bar, steam/ethanol 5 mol/mol, and O2/ethanol 0.86 mol/mol. In these conditions, 3.95 mol H2/mol ethanol is produced with 0 kJ/mol ethanol.
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Ethanol , Natural Gas , Renewable Energy , Hydrogen , Simulation Exercise , Models, AnatomicABSTRACT
M701 is a bispecific CD3/EpCAM T-cell engager antibody for the treatment of malignant ascites. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively describe and predict the antitumor effect of M701 in human colorectal cancer xenograft mice. We developed the M701 PK model based on plasma concentration data after i.v. administration. A tumor growth model for human colorectal cancer xenograft was developed to evaluate the antitumor effect of M701. We additionally simulated the inhibitory effect of M701 on tumor volume under different dose regimens based on a PK/PD model. A two-compartment model was developed to predict the PK in human colorectal cancer xenograft mice. The relationship between the M701 concentration and tumor growth inhibition was characterized by a combined Simeoni tumor growth/transit compartment model. The estimated pharmacodynamic parameters were related to the tumor growth characteristics λ0 (0.212 d-1) and λ1 (0.044 7 cm3·d-1), to the drug potency k2 (0.071 5 mL·ng-1·d-1), and to the kinetics of tumor cell death k1 (2×10-5 d-1). A model visual predictive check showed that both the PK model and the tumor growth model closely fit the observed data. Simulated tumor growth after administration of M701 (0.5 mg·kg-1 every 6 days and 0.25 mg·kg-1 every 3 days) could be effectively inhibited. This population PK/PD model of M701 provides insight into the antitumor effect of M701 and supports the further therapeutic development of M701.
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The subpulmonary ventricular exclusion (Fontan) could effectively improve the living quality for the children patients with a functional single ventricle in clinical. However, postoperative Fontan circulation failure can easily occur, causing obvious limitations while clinically implementing Fontan. The cavopulmonary assist devices (CPAD) is currently an effective means to solve such limitations. Therefore, in this paper the
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Child , Humans , Algorithms , Feedback , Heart-Assist Devices , Hemodynamics , Models, CardiovascularABSTRACT
Alzheimer's disease (AD) is a degenerative neurological disease with unclear pathogenesis. The disease progress/trajectory of AD patients can be adequately described by establishing quantitative pharmacological disease progression model. Integrating biomarker information into the model can provide more insight to understand the potential pathological mechanisms and facilitate the optimization of future trial design. Several empirical and semi-mechanism disease progression models have been published. This mini-review is expected to offer some references for the further AD clinical research and new drug development.
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Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.
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Population pharmacokinetics (PopPK) is an analytical method that can quantify the variability of drug concentration among individuals. It is widely used in various stages of new drug researches from non-clinic to clinic. With the rapid development of PopPK, more and more sponsors are keen to comprehensively analyze the in vivo processes of new drugs as well as its influencing factors using modeling and simulation methods. Several guidelines have been issued to recommend the use of PopPK in China. However, no explicit requirement of PopPK study report has been issued for regulatory application. This article conducts a preliminary discussion on new drug PopPK study and its reporting format and content, with reference to the requirements in relevant guidelines as well as previous review experiences, for the discussion or reference of industries and researchers.
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The prevalence of cardiovascular disease in our country is increasing, and it has been a big problem affecting the social and economic development. It has been demonstrated that early intervention of cardiovascular risk factors can effectively reduce cardiovascular disease-caused mortality. Therefore, extensive implementation of cardiovascular testing and risk factor screening in the general population is the key to the prevention and treatment of cardiovascular disease. However, the categories of devices available for quick cardiovascular testing are limited, and in particular, many existing devices suffer from various technical problems, such as complex operation, unclear working principle, or large inter-individual variability in measurement accuracy, which lead to an overall low popularity and reliability of cardiovascular testing. In this study, we introduce the non-invasive measurement mechanisms and relevant technical progresses for several typical cardiovascular indices (e.g., peripheral/central arterial blood pressure, and arterial stiffness), with emphasis on describing the applications of biomechanical modeling and simulation in mechanism verification, analysis of influential factors, and technical improvement/innovation.
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Humans , Arterial Pressure , Biomechanical Phenomena , Blood Pressure , Blood Pressure Determination , Reproducibility of Results , Risk FactorsABSTRACT
Industrial fermentation is the basic operation unit of industrial biotechnology in large-scale production. Mathematical simulation of microbial cells and their reactors will help deepen the understanding of microorganisms and fermentation processes, and will also provide solutions for the construction of new synthetic organisms. In this paper, the characteristics of industrial fermentation system, the development of mathematical simulation, the classification, characteristics and functions of mathematical models are described in depth, and the development trend of whole fermentation system simulation is prospected.
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Biotechnology , Fermentation , Industrial Microbiology , Models, BiologicalABSTRACT
Under the traditional “empirical trial design”,innovative drug development cannot make comprehensive use of the existing information from previous studies.The development efficiency is low.And it is easy to cause safety issues.Therefore,it is particularly necessary to explore and establish new models,more efficient and safer strategies for the clinical development of innovative drugs.In recent years,the “knowledgeable” clinical research strategy for new drug has been proposed and practiced by the FDA and EMEA.It employed the model and the simulation technology to quantitatively analyze and predict exposure/response relationships of innovative drug and its influence factors in patients.It helped in obtaining sufficient information from clinical data at the same time,to minimize the required number of subjects,and to ensure the safety of subjects in clinical trials.
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Objective To establish a three-dimensional(3D) finite element model of cervical vertebrae (C1-7),and study its biomechanical properties under muscle force by cervical traction,so as to provide references for clinical treatment.Methods On the basis of nonlinear finite element model of normal cervical vertebrae and combined with clinical traction methods,cervical traction at the extension angle of 0°,10°,20°,30°,40° under the same traction weight,was simulated by finite element analysis (FEA) software to obtain and select the joint force and muscle force that were appropriate for FEA on the model.Results In the process of cervical extension by traction,under the muscle force,the average maximum equivalent stress of cervical vertebrae,intervertebral disc and uncovertebral joints increased by 4.86,1.79,0.69 MPa,respectively,and the average maximum relative displacement of cervical vertebrae in sagittal and vertical axis direction increased by 1 1.1,1.26 mm,respectively.The biomechanical properties of cervical traction were similar to the FEA results reported in the literature.Conclusions Neck muscles play an active role in promoting the stress and displacement of cervical vertebrae,intervertebral discs and uncovertebral joints and it should be taken into consideration when performing cervical traction in clinic.In addition,the traction angle should not be too large:0.-20. is generally recommended as a relatively safe angle range at the initial stage.
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The purpose of this simulation study is to explore the limitation of the population PK/PD analysis using data from a clinical study and to help to construct an appropriate PK/PD design that enable precise and unbiased estimation of both fixed and random PD parameters in PK/PD analysis under different doses and Hill coefficients. Seven escalating doses of virtual drugs with equal potency and efficacy but with five different Hill coefficients were used in simulations of single and multiple dose scenarios with dense sampling design. A total of 70 scenarios with 100 subjects were simulated and estimated 100 times applying 1-compartment PK model and sigmoid E(max) model. The bias and precision of the parameter estimates in each scenario were assessed using relative bias and relative root mean square error. For the single dose scenarios, most PD parameters of sigmoid E(max) model were accurately and precisely estimated when the C(max) was more than 85% of EC₅₀, except for typical value and inter-individual variability of EC₅₀ which were poorly estimated at low Hill coefficients. For the multiple dose studies, the parameter estimation performance was not good. This simulation study demonstrated the effect of the relative range of sampled concentrations to EC₅₀ and sigmoidicity on the parameter estimation performance using dense sampling design.
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Bias , Clinical Study , Colon, SigmoidABSTRACT
Objective To establish a three-dimensional(3D) finite element model of cervical vertebrae (C1-7),and study its biomechanical properties under muscle force by cervical traction,so as to provide references for clinical treatment.Methods On the basis of nonlinear finite element model of normal cervical vertebrae and combined with clinical traction methods,cervical traction at the extension angle of 0°,10°,20°,30°,40° under the same traction weight,was simulated by finite element analysis (FEA) software to obtain and select the joint force and muscle force that were appropriate for FEA on the model.Results In the process of cervical extension by traction,under the muscle force,the average maximum equivalent stress of cervical vertebrae,intervertebral disc and uncovertebral joints increased by 4.86,1.79,0.69 MPa,respectively,and the average maximum relative displacement of cervical vertebrae in sagittal and vertical axis direction increased by 1 1.1,1.26 mm,respectively.The biomechanical properties of cervical traction were similar to the FEA results reported in the literature.Conclusions Neck muscles play an active role in promoting the stress and displacement of cervical vertebrae,intervertebral discs and uncovertebral joints and it should be taken into consideration when performing cervical traction in clinic.In addition,the traction angle should not be too large:0.-20. is generally recommended as a relatively safe angle range at the initial stage.
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Objective To establish a three-dimensional(3D) finite element model of cervical vertebrae (C1-7),and study its biomechanical properties under muscle force by cervical traction,so as to provide references for clinical treatment.Methods On the basis of nonlinear finite element model of normal cervical vertebrae and combined with clinical traction methods,cervical traction at the extension angle of 0°,10°,20°,30°,40° under the same traction weight,was simulated by finite element analysis (FEA) software to obtain and select the joint force and muscle force that were appropriate for FEA on the model.Results In the process of cervical extension by traction,under the muscle force,the average maximum equivalent stress of cervical vertebrae,intervertebral disc and uncovertebral joints increased by 4.86,1.79,0.69 MPa,respectively,and the average maximum relative displacement of cervical vertebrae in sagittal and vertical axis direction increased by 1 1.1,1.26 mm,respectively.The biomechanical properties of cervical traction were similar to the FEA results reported in the literature.Conclusions Neck muscles play an active role in promoting the stress and displacement of cervical vertebrae,intervertebral discs and uncovertebral joints and it should be taken into consideration when performing cervical traction in clinic.In addition,the traction angle should not be too large:0.-20. is generally recommended as a relatively safe angle range at the initial stage.
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Objective To establish a three-dimensional(3D) finite element model of cervical vertebrae (C1-7), and study its biomechanical properties under muscle force by cervical traction, so as to provide references for clinical treatment. Methods On the basis of nonlinear finite element model of normal cervical vertebrae and combined with clinical traction methods, cervical traction at the extension angle of 0°, 10°, 20°, 30°, 40° under the same traction weight, was simulated by finite element analysis (FEA) software to obtain and select the joint force and muscle force that were appropriate for FEA on the model. Results In the process of cervical extension by traction, under the muscle force, the average maximum equivalent stress of cervical vertebrae, intervertebral disc and uncovertebral joints increased by 4.86, 1.79, 0.69 MPa, respectively, and the average maximum relative displacement of cervical vertebrae in sagittal and vertical axis direction increased by 11.1, 1.26 mm, respectively. The biomechanical properties of cervical traction were similar to the FEA results reported in the literature. Conclusions Neck muscles play an active role in promoting the stress and displacement of cervical vertebrae, intervertebral discs and uncovertebral joints and it should be taken into consideration when performing cervical traction in clinic. In addition, the traction angle should not be too large: 0°-20° is generally recommended as a relatively safe angle range at the initial stage.
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BACKGROUND: A number of molecularly targeted agents in oncology are tested in clinical studies in combination with conventional chemotherapy and/or radiotherapy. There is the possibility that the pharmacokinetics and dynamics of these targeted agents may be different when administered alone as against when administered in combination with other agents. AIM: The aim of this study is to understand the effects of addition of combination agents on the pharmacokinetics of a new, investigational, cyclin dependent kinase inhibitor anti‑cancer drug (Compound A) using population pharmacokinetic (pop‑PK) analysis. MATERIALS AND METHODS: Integrated pop‑PK analysis of data obtained from multiple phase I/II studies of Compound A, given alone or in combination with other agents. RESULTS: A two compartmental model was found suitable to explain the pharmacokinetics of Compound A. No statistically significant influence of patient covariates or combination agents on the pharmacokinetic parameters of the central compartment was detected up to a significance level of 0.01. Model evaluation showed that the parameter estimates are stable and that the variability in the data was well reproduced by the model. CONCLUSIONS: This study represents the first time that a pop‑PK analysis was performed in India for a targeted anti‑cancer agent being developed in India. Such an analysis is useful to not only understand the influence of patient covariates and combination agents on the pharmacokinetics of a new investigational agent, but would also be valuable in the simulation of later phase clinical trials for the agent under development.