Upcoming Simcyp® Workshops

The main aim of this focused workshop is to demonstrate the application of best practices in developing PBPK models, and to indicate how to qualify and refine model performance. Various case studies, including some real-life examples, will be presented.

The case studies will cover various elements of model development including DDIs, special populations, transporters, and different formulations. Optimal in vitro and clinical data sets will be discussed. Participants will learn how to choose the most suitable models and also investigate the impact of various relevant assumptions on model performance. Requirements for regulatory submissions will also be discussed. It is assumed that the participants are familiar with the fundamentals of PBPK modeling and have hands-on experience.

Key aspects covered in this course:

• Quick overview of models within the Simcyp Simulator
• Model selection and how to pick the most suitable models
• What are the most appropriate in vitro data
• Leveraging clinical data to verify and refine PBPK model performance
• Application of special population models
• Application of sensitivity analysis in assessing the impact of uncertain parameters

This workshop will explain the principle of therapeutic protein pharmacokinetic and pharmacodynamic modelling. Distribution, clearance, FcRn recycling, targetmediated drug disposition (TMDD), and subcutaneous absorption will be covered for monoclonal antibodies and other therapeutic proteins. Additionally, the suppression of CYP enzymes by cytokines and thus interactions between biologics and small molecule drugs will be simulated. Participants will learn how to apply these models using case studies.

• The use of minimal physiologically-based pharmacokinetic models for both mAbs and other therapeutic proteins
• The use of the full PBPK models for therapeutic proteins available within the Simulator
• Prediction of pharmacokinetics of therapeutic proteins in populations as well as in an average individual
• Utilization of the 2-pore calculation to predict the distribution of therapeutic proteins
• Use of the allometric calculator tool
• The effect of FcRn affinity and charge state on the pharmacokinetics of monoclonal antibodies
• Demonstrating the utility of the target mediated drug disposition models (TMDD) within the Simulator
• The use of TMDD models that can account for the shedding of target from the cell surface into the interstitial space and plasma
• Linking the biologics/TMDD models to simulate pharmacodynamic effect
• Modelling the interaction between biologics and small molecule drugs
• Modelling subcutaneous / intramuscular absorption of therapeutic proteins

The aim of this workshop is to provide an overview of PBPK models to predict the pharmacokinetics of complex large molecules such as antibody-drug conjugates (ADCs), bispecific antibodies, and oligonucleotides. Of special interest will be the prediction of therapeutic protein concentration in the tumour and the application of a tumor model. Furthermore, the simulation of large molecules in the monkey and pediatrics will be discussed. Several model applications will also be presented.

Key aspects covered in this course:

• Use of minimal and full physiologically-based pharmacokinetic (PBPK) models for antibodydrug conjugates (ADC) and their link to the small molecule Simulator
• Utilization of the tumor model for large molecules to predict the drug concentration at the tumor site
• Introducing the concept of bispecific antibodies and the use of target-mediated drug disposition (TMDD) models for bispecific antibodies
• Introduction to modelling oligonucleotides
• Modelling and simulation of therapeutic proteins in the monkey and translation to humans
• Large molecules disposition in children
• Application of the large molecule models at different stages of drug development

The ABC of modeling drug transporter data—mechanistic approaches to predict the impact of drug transport proteins on ADME/pharmacokinetics and toxicity.

• Revisiting common in vitro transporter-based assays
• Characterization of key parameters required to model in vitro data
• Understanding complex data sets generated from in vitro assays
• Approaches to optimizing and modeling complex data sets derived from in vitro assays
• Scaling of in vitro data for gut, liver, brain, and kidney to in vivo
• Practical examples involving the applications of the modeling approach to answer observations related to: oral bioavailability, renal clearance, hepatic clearance, drug-drug interactions, and brain disposition
• Predicting impact of transporters on tissue-drug concentrations (efficacy/toxicity)
• Impact of population variability on transporter-based drug disposition
• Approaches to handling genetic variations
• Modeling the impact of transporters on pharmacodynamics

The course is ideal for modelers and scientists (both bench and clinical) who want to enhance their knowledge of mechanistic approaches to predicting the impact of drug transport proteins on ADME/ pharmacokinetics and toxicity.

Predicting age related changes to pharmacokinetics (PK) and drug-drug interactions including associated variability—linking this information to drug response in the pediatric population. Participants will learn how PK behavior can be modeled in neonates, infants, and children and how it can be linked to PD. Hands-on exercises explore how this valuable information is relevant to early and informed decisions to assist in the improved design of pediatric clinical studies.

Key aspects covered in this course:

• The impact of developmental physiology and ontogeny of drug elimination systems
• How changing ontogeny influences the level of drug-drug interactions in pediatrics
• In vitro-in vivo extrapolation (IVIVE) and how it applies to neonates, infants, and children
• Development and utilization of a pediatric full physiologically-based pharmacokinetic (PBPK) model
• How the PBPK model can be linked to PD
• Handling unknown values for pediatric PBPK/PD model parameters
• Pediatric oral drug absorption
• Specialized study design considerations (eg, formulation, diet)
• The role of modeling and simulation in pediatric drug development

Mechanistic oral absorption modelling and prediction of bioavailability for drug products incorporating inter-subject variability. Theory and applications of the Simcyp Advanced Dissolution, Absorption, and Metabolism (ADAM) Model.

• Gut wall permeability and first-pass metabolism
• Drug solubility, dissolution, precipitation and supersaturation
• Oral drug absorption incorporating food effects
• Bioavailability and the impact of physiology and dosage form including salts
• Entero-hepatic recirculation
• Inter-individual variability assessment

Application of the SIVA Toolkit to the modeling of in vitro experiments to confirm and/or estimate parameters for PBPK simulations with a case studie; mechanistic modeling of dissolution and precipitation in USP 2, USP 4, serial dilution, transfer and biphasic systems.

This course broadens the range and utilization of in silico-based mechanistic prediction and analysis of drug absorption after oral delivery, including the development of mechanistic physiologically based in vitro-in vivo correlations (IVIVCs), virtual bioequivalence (VBE) concepts, and application of biopharmaceutic IVIVE using the SIVA Toolkit. We strongly recommend attending Oral Absorption I before taking this workshop.

Key aspects of the course:

• Recognize the opportunities and challenges in applying quantitative modelling and simulation tools in the field of oral drug formulation development.
• Development of mechanistic physiologically based in vitro-in vivo correlations (IVIVCs) for oral dosage forms.
• Virtual bioequivalence for oral dosage forms, theory and application.
• Application of the SIVA Toolkit to IVIVE of dissolution including the P-PSD approach.
• Mechanistic modelling of excipient binding to API with example.
• Expanding the Simcyp absorption model to PD/scripting – modeling of acid-reducing agents (ARAs) and other applications.

This workshop will provide an in depth overview of generation of populations for mechanistic PBPK, focusing on key covariates to inform prediction of pharmacokinetics in healthy as well as disease populations.

Key aspects of the course:

• Building populations and Correlated Monte Carlo Sampling
• Age matching clinical trial design
• Bridging Studies – Japanese and Chinese Populations
• Time varying population parameters – Pregnancy
• Mechanistically accounting for impact of Disease
• Renal Impairment, Cirrhosis populations
• Oncology populations

In this focused workshop you will use the dynamic models within the Simcyp Simulator to prioritise compounds for progress to the next stage of development using information available in early drug discovery. You will use information on clearance, absorption, tissue distribution and DDI liability to inform compound selection. Finally, from the originally large database, only a few compounds will be selected for FIH and the simulation results compared with available clinical data.

The case studies will cover various elements of model development including DDIs, special populations, transporters, and different formulations. Optimal in vitro and clinical data sets will be discussed. Participants will learn how to choose the most suitable models and also investigate the impact of various relevant assumptions on model performance. Requirements for regulatory submissions will also be discussed. It is assumed that the participants are familiar with the fundamentals of PBPK modeling and have hands-on experience.

During the workshop you will be shown how to use a number of tools including:

• SIVA toolkit
• Batch Processor
• Compound import
• Sensitivity analysis
• Parameter estimation
• Using R to run Simcyp
• Retrograde calculator

Predicting and evaluating complex DDIs—application of the Simcyp Population-based Simulator to real-life cases.

Participants will learn good practices in combining data from both in vitro and clinical studies, whilst gaining experience in using such data within physiologically-based dynamic models to evaluate the DDI liability of drug candidates.

• Static vs. dynamic models (including discussion around regulatory guidance)
• Metabolic and transporter mediated DDIs
• Competitive inhibition, mechanism-based inhibition, induction, and suppression
• Complex DDIs involving combined interaction mechanisms and multiple inhibitors (including inhibitory metabolites)
• Importance of in vitro study design
• The role of non-hepatic metabolism in DDIs
• Use of parameter estimation and sensitivity analysis
• Optimal clinical study design
• Special populations—identification of individuals at risk of DDI

A systems pharmacology approach to modeling and simulation: Accelerating model building and covariate recognition in drug development by combining top-down and bottom-up modeling of pharmacokinetics linked to drug response.

The workshop covers the concepts and the practical applications of integrating in vitro data and physiological knowledge with clinical observations for the purpose of estimating unknown/uncertain model parameters. Delegates will work through different parameter estimation examples using fitting tools and explore various PD models.

Key aspects covered in this course:

• The theoretical basis for combining bottom-up and top-down modeling and simulation
• Parameter estimation:
• Step-by step guidance on data entry, fitting, and interpretation of results
• Simultaneous fitting of PK and PD parameters
• Covariate recognition
• Pharmacodynamics:
• Models available
• Use of preliminary clinical data to model and simulate various covariate effects (eg, genotypic/phenotypic differences, effects of diseases such as renal impairment or cirrhosis)
• PD at the relevant effect site (eg, liver)
• Custom scripting of user-defined PD models

The aim of the workshop is to present how mechanistic M&S can be used for the assessment of a drug’s pro-arrhythmic potency within target populations. Cardiac Safety Simulator can be used in the early stage of the drug development as a screening tool even in situations where no in-vitro data are available, or later at the clinical level to assess drug-drug or drug-physiology interactions.

The case studies will cover various elements of cardiac safety assessment including in vitro ion channels inhibition, clinical surrogates of cardiac safety and role of population variability all within the framework of simulated clinical trials. Participants will learn how to choose the most suitable models and also investigate the impact of various relevant assumptions on model performance.

Key aspects covered in this course:

• Quick overview of models within the Simcyp CSS
• What are the most appropriate in vitro data for the cardiac safety testing and their simulation
• Application of population models for the drug-physiology interaction assessment

Broadening the range and utilization of in silico-based mechanistic prediction and analysis of drug absorption after non-oral application. Mechanistic modeling of the topical drug application, development of mechanistic physiologically-based in vitro-in vivo correlations (IVIVCs), and virtual bioequivalence (VBE) concepts.

Key aspects covered in this course:

• Recognize the opportunities and challenges in applying quantitative modelling and simulation tools in the field of non-oral drug formulation development.
• The use of Multi-Phase Multi-Layer (MPML) MechDermA model for simulating the absorption of drug from the skin
• Development a physiologically based pharmacokinetic framework for modelling in vitro and in vivo skin permeation of topical/transdermal products – establishing dermal in vitro in vivo extrapolation
• Utilization of IVPT module for the in vitro skin permeation simulation and further extrapolation to in vivo situation (IVIVE)
• Different types of topically formulations – solutions, emulsions (O/W, W/O), emulsions with solid particles, suspensions, patches
• Understanding and modeling the metamorphosis of the topical formulations when applied on the skin surface
• The use of MechVAM and MechRAM models for simulating the absorption of drug after vaginal and rectal application, specifically.
• Development of mechanistic physiologically-based in vitro-in vivo correlations (IVIVCs) for dermally applied with discussion around case studies
• Virtual bioequivalence for dermally applied with discussion around case studies

Certara UK Limited is running a Simcyp hands-on workshop discussing the changes to pharmacokinetics during pregnancy and the prediction of pharmacokinetics (including in the milk) during lactation. Population based Physiologically Based Pharmacokinetic (PBPK) approach will be utilized to describe the pharmacokinetics during pregnancy and lactation and to determine population variability.

Key aspects covered in this course:

• Maternal and fetal gestational age-dependent physiological changes
• Prediction of maternal and fetal drug pharmacokinetics
• Ways of incorporating ex vivo experimental data on transplacental kinetics within the PBPK model
• Handling gestational age-varying covariates during simulation
• Prediction of PK in breastfeeding mothers and milk exposure using lactation models
• Prediction of infant dose for breastfed infant
• To understand the requirements in developing for maternal/fetal and lactation PBPK models using hands-on examples.
• To get familiar with different pregnancy/lactation PBPK models assumptions within the Simulator, interpretation of the results to make recommendations using clinical examples.
• To be able to integrate experimental results within the pregnancy and lactation PBPK framework.
• Upon completion, participants should be able to recognize opportunities and challenges in applying quantitative modelling and simulation tools in the field of perinatal pharmacology.
• Upon completion, participants should be able to utilise the advantages of PBPK models in providing information during drug development and in clinical settings.