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GastroPlus 9.8 - Brochure 2021.pdf

The GastroPlus PBBM / PBPK modeling and simulation package – supporting internal research through regulatory filings…

GastroPlus is a mechanistically based, validated software package that

simulates absorption, pharmacokinetics, pharmacodyanmics, and DDIs

in human and animal populations.

As a researcher in the life sciences space, you can’t measure everything as a project winds its way through the R&D process. With the data that is being generated, you’re expected to make informed decisions as quickly as possible. A wrong one sets you back severely, both in terms of time, money, and getting to market. Now, more than ever, it is important to consider incorporating new technology across your company – like PBPK & PBBM modeling.

The GastroPlus PBBM / PBPK modeling and simulation package – supporting internal research through regulatory filings…

What if it were possible to:

Integrate the data which has been collected and, within the context of a virtual animal or human model, gain unique insights that improve your chances for success?

Run simulations for different scenarios to avoid costly surprises?

Utilize the outputs from these models to potentially waive expensive studies requested by regulatory agencies?

It’s possible to do this, and more, with the GastroPlus PBPK modeling platform.

GastroPlus is a mechanistically based simulation software package that simulates intravenous, oral, oral cavity, ocular, inhalation, dermal, subcutaneous, and intramuscular absorption, biopharmaceutics, pharmacokinetics, and pharmacodynamics in humans and animals. This smoothly integrated platform combines a user-friendly interface with powerful science to help you make faster and more informed project decisions!

GastroPlus has been separated into modules to make it easier for companies to license only the features they need in each department. The 10 modules currently available are:

Drug Drug Interaction
PBPKPlus™
ADMET Predictor®
Additional Dosage Routes
Metabolism & Transporter
Biologics
Optimization
PDPlus™
PKPlus™
IVIVCPlus™

What are we providing with GastroPlus?

From the beginning, a conscious decision has been made to carefully implement the best theories and develop novel approaches within the GastroPlus physiologically-based pharmacokinetics (PBPK) & physiologically based biopharmaceutics modeling (PBBM) models. This dedication to science is a major reason why our predictions are consistently ranked #1 in independent comparisons. You provide the (limited) data, GastroPlus provides everything else:

Simple, intuitive user interface
Model customization
High-quality plots & figures for reporting purposes
Excellent customer support

How is GastroPlus being applied?

The GastroPlus PBPK modeling and simulation platform has been utilized by companies across various industries and departments since 1998. Some of the routine applications include:
Screening compound libraries through the QSAR & PBPK marriage to prioritize in vivo testing
Predicting first-in-human (FIH) and animal doses with best-in-class IVIVE methods
Supporting animal or human risk assessment studies
Simulating steady-state and dynamic drug-drug interactions (DDI) for regulatory submissions
Building PBPK, PBBM, PD models to estimate efficacious dose levels
Assisting with Quality by Design (QbD) implementation to define product specifications
Deconvoluting in vivo dissolution for mechanistic IVIVCs
Understanding food effect differences
Conducting virtual population PK & PBPK studies & bioequivalence trials
Identifying appropriate dose levels and dosing regimens in diseased & pediatric populations
… and more!

请回到该产品介绍顶部，查看模块简介、应用案例、资料文献、专题培训

GastroPlus 9.8 - Brochure 2021.pdf

PBPKPlus™

What is the PBPKPlus™ Module?

Ranked as the #1 PBPK software for In Vitro-In Vivo Extrapolation (IVIVE) & PBPK modeling by Pfizer!

(Cole et al., 2nd Asian Pacific Regional ISSX Meeting, May 2008, Shanghai, China)

NEW! Improved handling of covariates in Population Simulator.

NEW! Additional disease physiology groups (obesity, renal impairment)

NEW! Clearance mechanisms in blood compartments

Upgraded! Infant PBPK models – easily perform pediatric PBPK modeling to capture the pharmacokinetics and pharmacodynamics in infants as young as 16 weeks premature, with automatic scaling of physiological parameters (e.g., hematocrit, plasma protein levels) with age!

The PBPKPlus™ Module extends GastroPlus™ to define a physiologically based pharmacokinetic (PBPK) model consisting of various tissues. You can easily simulate the distribution and elimination of compound throughout the body and track concentrations in any tissue. Any tissue can employ fixed intrinsic clearance and with the Metabolism and Transporter Module, saturable (Michaelis-Menten) metabolism and transport (influx and efflux) can be incorporated. Tissues can be defined as needed, or default models can be used with a standard set of compartments:

Adipose
Arterial blood
Brain
Gut
Heart
Lungs
Liver
Muscle
Skin
Spleen
Reproductive organs
Venous blood
Kidney
Yellow marrow
Red marrow

Customize your PBPK model by treating any tissue as either a perfusion-limited or permeability-limited model, and quickly add/delete tissues as needed – all without writing any equations using the GastroPlus PBPK software!

NEW! Transporter-based IVIVE: automated scaling of permeability across tissues using a single parameter! Check out the Resource Center for more details on the approach and how it can be applied to scale across species or populations!

The PBPKPlus™ Module also provides:

Generation of physiological model parameters (tissue weights and volumes, perfusion rates, etc…) with our built-in PEAR Physiology™ (Population Estimates for Age-Related Physiology). Current physiology models are:

Human (American or Asian, male or female, healthy, liver disease, obesity, renal impairment – based on age)
Infant/pediatric groups
Rat
Dog
Mouse
Monkey
Rabbit
Minipig

Run population PBPK simulations (through the Population Simulator™) based on parameter variances in a sample population. Generate up to 2500 subjects in a single, Monte Carlo-based run, or reuse existing populations to perform virtual crossover studies. Define your own age & BMI range, % male vs. female, and the number of “virtual” subjects you wish to create

Updated! Covariates for gastrointestinal physiology and age/gender of virtual PBPK subjects created

Novel methods for estimating tissue partition coefficients in PBPK models from logD, pKa, plasma protein binding, and Rbp – only GastroPlus has the upgraded “Rodgers-Rowland” (Lukacova) method, developed in collaboration with Roche

Physiological models for kidney, including glomerular filtration and reabsorption

Parameter Sensitivity Analysis of nearly all physiological, physicochemical, pharmacokinetic, and metabolism/transporter parameters

Fit models to in vivo data in single or multiple compartments (Optimization Module required) – use plasma/tissue concentrations, amount excreted in urine, etc…

Link pharmacodynamic effect directly to drug concentration in specific tissues (PDPlus™ Module required)

Mechanistic transport of drug from hepatocytes to bile in liver, modeled either as a linear process or through carrier-mediated transport (Metabolism and Transporter Module required)

Report-quality plotted output of all time-dependent results in all tissues in your PBPK models – can be captured through any simulation run (Parameter Sensitivity Analysis, Batch, or Population Simulator)

PKPlus™

What is PKPlus™?

The PKPlus™ Module extends GastroPlus® to rapidly estimate pharmacokinetic (PK) parameters for noncompartmental analysis (NCA), along with 1-, 2-, & 3-compartment PK models from pharmacokinetic studies (IV and/or oral) without the need to run full simulations. The optimization and selection of the appropriate compartmental PK model is automated from a single mouse click, but you control which parameters are transferred back to the main GastroPlus model.

The fitted parameters include PK properties, first order absorption rate, bioavailability and absorption lag time (if both IV and oral data are included in fitting). Required inputs are plasma concentration vs. time profiles, dose, body weight and infusion time (if applicable). Compartmental PK models can be fitted to single IV or oral data as well as across multiple plasma concentration vs. time profiles – IV, oral, or combination of IV and oral as well as different dose levels. Linear or saturable clearance models can be easily selected.

Full statistics, including Akaike Information Criterion and R^2, are provided for all models. Residual information is also captured and can be plotted. Once finished in PKPlus, the parameter values of the selected model can be easily transferred back to the main GastroPlus model, and report-quality outputs can be captured and saved.

In the figures provided you will see:

Plotting of absolute, log, and residuals for each model is selected with a mouse click, allowing rapid comparison of models.
2-compartment PK model for midazolam fitted across IV and three oral doses.
Residuals plot for 2-compartment PK model for midazolam fitted across IV and three oral doses.

Metabolism & Transporter

What is the Metabolism and Transporter Module?

NEW! When linked with the upgraded ADMET Predictor® Module, predict nonlinear pharmacokinetics for CYP metabolism, and have the Enzyme Table automatically populated with the correct locations and units!

Updated! Enzyme and transporter expression levels across species – including UGTs, SULTs, and transporters in various tissues in PBPK models!

Enhanced! Metabolite tracking options!

The Metabolism and Transporter Module is an optional module that extends the capabilities of GastroPlus® to include nonlinear pharmacokinetics into any compartment (gut, liver, and/or any PBPK tissue), along with metabolite tracking. This module calculates Michaelis-Menten rates for gut and liver (or any PBPK tissue) metabolism and for carrier-mediated transport (influx or efflux – again, for any tissue in a PBPK model) based on input values for Vmax and Km.

You can provide Vmax and Km values for each enzyme/ transporter independently, or you can lump them into a single effective Vmax and Km, depending on your data. The distribution factors on the Physiology tab are automatically loaded for recognized gut enzymes and transporters, and provide the relative amounts of enzymes or transporters in the various ACAT™ gut model compartments. The Vmax and Km scale factors on the Pharmacokinetics tab are provided to allow fitting nonlinear kinetic models to your data.

The Metabolism and Transporter Module includes a Units Converter tool for easy transformation of a variety of your in vitro metabolism or transporter kinetic parameters into values and units that can be utilized by the GastroPlus PBPK model.

Define multiple metabolic/transport pathways, with enzymes and transporters placed into the tissues or organs of your choice. Also, easily link the formation of different metabolites in a single simulation – no limit on the number of metabolites you want to track!

Drug Drug Interaction

What is the DDI Module?

The DDI Module in GastroPlus® allows you to predict mechanistic and static drug-drug interactions (DDIs) among drugs and metabolites. The ability to accurately estimate potential DDIs in silico has several benefits for pharmaceutical companies:
Explore possible effects on the pharmacology and toxicology of drugs
Identify species-specific changes to estimate how a drug behaves in animals vs. humans
Investigate the safety profile of drugs that are co-administered prior to filing regulatory submissions with the FDA, EMA, and other agencies
With the DDI Module, calculating either mechanistic steady-state and/or dynamic drug interactions is managed through our easy-to-use interface. We provide a database of validated compound model files (>30) for which all relevant parameters (including reported Kis and full compartmental PK & PBPK models) are defined. Of course, you may predict DDIs among any drugs by simply entering the required inputs. As with other GastroPlus modules, there is no equation or code writing required.

What are some of the advantages to using the GastroPlus DDI Module?

NEW! Population Simulator™ linked with DDI predictions! Now incorporate variability between subjects in your dynamic simulations and see the impact on victim, perpetrator, and metabolite(s) concentrations and AUC ratios. Define your population (American, Asian, pediatric, etc…) and number of subjects (up to 2500) in your trial to start.
Once the simulations are completed, view the mean results and 90% confidence intervals for the concentration-time profiles and major endpoints (e.g., Cmax, AUC)

What else can we do with the GastroPlus DDI Module?

Transporter-based drug-drug interactions
Metabolic and/or transporter induction
Linked with the industry’s #1-ranked dissolution, absorption (ACAT™) model
Use with either 1-, 2-, or 3-compartment PK models or physiologically based pharmacokinetic models (PBPKPlus™)
Apply competitive and/or time-dependent inhibition kinetics by parent and/or metabolite(s)
Simulate DDIs for any species (human, beagle, rat, mouse, rhesus monkey, cymonologous monkey, minipig, rabbit, or cat)
Account for enzyme expression level differences in various populations (Caucasian and Asian)
Built-in tool to calculate the fraction metabolized (fm) from in vitro assays (rCYPs and microsomes are accommodated)

Incorporate nonlinear gut contributions to DDIs

Predict the inhibitor effect using simulated concentrations at the site of metabolism (gut, liver, or any PBPK tissue) for dynamic DDI simulations

Include the effects of multiple substrates on clearance of other substrates metabolized by the same enzyme

案例1： GastroPlus模拟药物在肠道中的浓度，豁免FDA要求的额外临床试验

新药评审中，FDA怀疑Pfizer的在研药物SR在肠中的浓度和该药物与P-gp和CYP3A4的Ki值相近，可能会与其他药物产生药物相互作用（DDI), 因此要求Pfizer增加额外的临床试验以测定该药在人肠中的浓度。

目的

Pfizer研究人员采用GastroPlus了在研药物SR在人体各肠段的肠腔和肠细胞中的药物浓度，以期豁免FDA要求的额外临床试验。

结果与方法

研究人员采用在研药物SR的理化性质、体外代谢、临床静注和口服的PK数据，通过GastroPlus建立并验证了PBPK模型，从而模拟SR在各肠段中的药时曲线。

模拟结果表明，在研药物SR在人体各肠段肠腔的浓度和肠细胞的浓度均远低于Ki值，因此产生药物相互作用的可能性很小。

结论

Pfizer提交该申请资料后，FDA也采用GastroPlus建模

并用该药物的临床PK数据进行模型的验证，最终认可了模拟的结果

并豁免了该药物额外的临床试验。

Ref: Hosea, N. (2009), AAPS Annual Meeting and Exposition, Los Angeles, CA, USA

案例2：采用GastroPlus进行种属间/种属内PK外推

已有数据

更昔洛韦及其前药缬更昔洛韦的理化性质、酶及转运体的动力学数据、动物、成人及儿童的PK数据等

目的

建立药物在动物、成人及儿童体内的PBPK模型，考察目标患者预测与观测的PK行为是否一致，以指导目标患者临床用药剂量的设置。

方法

通过GastroPlus构建药物在动物及人体的生理模型，用已有的PK数据验证和修正模型参数与公式，确保模型的准确性；
将模型用于对目标患者体内PK的预测，考察按照成人相同ADME过程的参数设置是否能准确预测目标患者的PK；若能体现出相同的ADME过程，以此分析目标患者的临床剂量是否需要进行调整和优化。

结果

GastroPlus的PBPK模型可很好地反映各个种属观测的PK结果，预测结果和试验观测值较为一致；
目标患者表现与其他人群相似的PK与PD行为，且通过PBPK模型未发现有其它的生理机制将影响该药物在体内的暴露；
已设定的给药方案在目标人群中有较好的PK与PD行为，因此后期临床试验用药时，目标患者可采用该给药剂量的临床方案。

Ref：AAPS J. 2016 Nov; 18(6): 1453-1463. Clin Pharmacol Ther. 2016 Dec; 100 (6): 761-769.

案例3： GastroPlus考察粒径变更后的生物等效性，豁免FDA要求的BE试验

杨森制药在卡格列净的药品开发中，原料药API结晶工艺从原来的非粒径工程NPE变更为粒径工程PE，导致API的粒径可能产生变化；
I期，II期及IIIa期试验采用的是非粒径工程NPE的API，而IIIb期采用的是粒径工程PE的制剂；
FDA认为该药物临床药理学及说明书生物药剂学性质部分的描述是根据非粒径工程NPE API开展的I期临床试验数据获得的，而IIIb计划采用粒径工程PE API开展试验，需补充这两种制剂的相对生物利用度试验。

目的

通过GastroPlus建模与模拟的结果，考察这两种制剂是否生物等效，以期豁免补充的临床试验。

方法

结合卡格列净的理化、代谢及PK数据搭建该药物的PK模型，并验证模型的准确性；
进行粒径变化的参数敏感性分析，分析确保生物等效的粒径范围；
开展虚拟生物等效性试验，考察不同粒径工程的制剂生物等效性的可能性。

结果

参数敏感性分析显示API的平均粒径是决定该制剂能否生物等效的主要因素，而与给药剂量的相关性较小；
虚拟生物等效性考察结果表明：当粒径小于40 µm且在临床常用剂量下，采用PE API和NPE API制备的两种片剂，其结果为生物等效；
杨森制药将结果提交给FDA后，FDA对模拟结果进行验证和审核后，认可了模拟结果并豁免了该补充的临床试验。

Ref: Christophe Tistaert , Janssen, AAPS Meeting, 2015

案例4：In vitro-in vivo correlation (IVIVC，体内外相关性)

已有数据

某BCS I类药物的理化性和PK参数，实测的不同口服制剂的血浆药时曲线(控释)，实测相应制剂的体外溶出数据。

目的

采用不同方法建立A级IVIVC模型，并进行内部与外部验证考察相关性模型建立的准确性；
探究建立的IVIVC模型是否可以用于预测释放机制不同的处方的体内PK曲线。

方法

在GastroPlus中，分别建立不同制剂的PK模型，并分别加载实测的体外及反卷积的体内释放曲线，选择机制性反卷积方法建立体内外相关性。

结论

采用GastroPlus的机制性反卷积法 (Mechanistic Absorption Model Deconvolution)可建立起符合法规要求的IVIVC模型；
GastroPlus的相关性模型外部验证预测范围更宽，可以准确预测释放机理相同其它几种受试制剂的体内PK曲线；
不同的相关性方法均无法准确预测释放机制不同的受试制剂体内PK曲线，即不同释放机制的制剂超出了所建立IVIVC模型的预测范围。

Ref：Pharm Res. 2013 Jan; 30(1): 179-90.

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导读

大阳集团娱乐网址777技术部精取了近年来GastroPlus在不同领域的应用文章，共13类。

分别为：GastroPlus在FDA等法规部门的应用；在PBPK、ACAT、PBBM 模型应用的综述；预测PK曲线或PK参数；在口服吸收、制剂开发等的应用；在IVIVC, IVIVR, BE考察的应用；在PK-PD结合模型的应用；在预测特定人群PK的应用；在预测药物相互作用DDI的应用；在考察食物效应的应用；在考特殊给药途径的应用；在毒理领域的应用；评估GastroPlus预测准确性的应用及中国用户采用GastroPlus发表的应用文章。

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