IVIVE Toolset

In vitro to in vivo extrapolation (IVIVE) frameworks are essential for translating in vitro ADME (absorption, distribution, metabolism, and excretion) data into meaningful predictions of in vivo pharmacokinetics or toxicokinetics. These frameworks play a central role not only in next-generation risk assessment (NGRA) but also in supporting key stages of drug development, including compound screening, lead optimization, and clinical translation. While high-quality in vitro data are essential, the true value of IVIVE lies in its ability to bridge the gap between in vitro assays and in vivo systems through robust and transparent scaling methods.

IVIVE approaches typically integrate both mechanistic and empirical scaling methods, depending on the level of understanding of in vitro-in vivo differences and the reliability and variability of the in vitro data. Hence, developing effective IVIVE frameworks requires a deep understanding of in vitro assay design, the underlying biochemical processes, and the structure and parameterization of physiologically based (pharmaco)kinetic – PB(P)K models.

Physiologically based biopharmaceutics modeling (PBBM) is a specific field of PBPK model applications that aims to establish the link between the formulation’s properties and in vivo performance.

This field of application of PBPK modeling is evolving at a fast-pace and offers the link between in vivo and in vitro to support pharmaceutical development in the selection of the best drug substance and product, as well as later in development in the establishment of manufacturing quality and controls.
Dissolution testing is often a key input in PBBM. Results from in vitro experiments characterizing drug substances and the formulation behavior (e.g., solubility, particle size, dissolution) can be linked to key ADME parameters and integrated into full PBPK models to predict PK exposure in plasma and/or specific tissues or organs.

These models can also be linked to Pharmacodynamic (PD) relationships to derive the impact of physicochemical, drug and formulation properties on safety and efficacy. The role of Physiologically Based Biopharmaceutics Modeling (PBBM) in drug development spans multiple stages, including supporting patient-centric design, guiding life cycle management, informing regulatory submissions, streamlining development processes, optimizing dosing strategies, enhancing study design, and aiding in formulation development and developability assessment.

What we can offer

At ESQlabs, our multidisciplinary team brings deep expertise in IVIVE and ADME science to develop and implement a wide range of IVIVE methodologies tailored for diverse end-uses:

Validation and Refinement of In Vitro ADME Assays
We use IVIVE frameworks to directly compare new or standard in vitro ADME assay results with in vivo ADME values. This enables assessment of an assay’s applicability to new chemical spaces or validation of novel in vitro assays using reference chemicals.

Preclinical Screening via IVIVE-Integrated High-
Throughput PB(P)K Models
By integrating in vitro ADME values into PB(P)K models, we provide in vivo pharmacokinetic predictions (e.g., fraction absorbed, bioavailability, half-life) before any animal or human testing, supporting early-stage screening and prioritization. This strategy allows for early de-risking and ranking of candidate compounds based on exposure profiles and PK liabilities.

Development of Next-Generation PBK (NGRA-PBK) Models for Chemical Safety Assessment
We specialize in PBK models parameterized exclusively with in vitro and in silico data, enabling the prediction of human or target animal toxicokinetics without the need for animal studies. This supports next-generation risk assessment and regulatory acceptance.

Clinical Dose Projection and First-in-Human Predictions
We apply IVIVE to guide dose selection in first-in-human studies by estimating key parameters such as hepatic clearance and oral absorption from in vitro data. This enables rational starting dose selection, it can be integrated in other modeling approaches and supports regulatory filings.

Route-to-Route Extrapolation
By linking in vitro absorption data to in vivo outcomes across different tissue barriers, we can extrapolate kinetic profiles from one exposure/administration route (where in vivo data exist) to scenarios involving alternative routes of exposure/administration.

Screening for Population Variability in ADME
Biological material from different populations (e.g. age or ethnic background) can be used in vitro to derive the ADME parameters be integrated through IVIVE in PB(P)K models. This integration involved tailoring the IVIVE and PB(P)K models to the specific purpose. This mechanistic approach enables the use of chemical-specific adjustment factors (CSAFs) for inter-individual variability of chemical safety, moving beyond default empirical factors. In the pharmaceutical field, it allows extrapolations between populations (e.g., pediatrics, geriatrics) and helps ensure predictions are tailored to the intended patient group.

Inter-Species Extrapolation for Chemical Safety Assessment and Drug Development
Our IVIVE-integrated approach allows for the derivation of chemical-specific safety factors for interspecies toxicokinetic differences, replacing default uncertainty factors with chemical-specific adjustment factors (CSAFs). In drug development, this approach supports rational species selection and dose projection in preclinical studies by identifying kinetic drivers of interspecies differences, enhancing the translation of preclinical findings to human scenarios.

Support for DDI Risk Assessment and Transporter Kinetics
We apply IVIVE methodologies to simulate drug-drug interactions (DDIs), incorporating transporter and enzyme kinetics (e.g., CYP, UGT, OATP, OCT). This supports risk assessments for inhibitors and substrates in development pipelines.

ESQlabs has specialized expertise in IVIVE applications such as hepatic clearance, oral absorption, membrane transporters, and placental transfer. Our workflows are seamlessly integrated with the Open Systems Pharmacology (OSP) Suite, with flexibility to implement IVIVE strategies in other open-source environments (e.g., R) depending on the project needs.

For advanced in vitro systems such as microphysiological systems (MPS), including organs-on-chip or microfluidic models, we collaborate with our dedicated MPS team to develop appropriate IVIVE frameworks.

In parallel with our IVIVE tool development, our team is actively engaged in advancing IVIVE processes within the OSP Suite and providing training to the OSP community.

Related publications and initatives

Application of High-Throughput PBPK Modeling to Develop an IVIVE Approach for Oral Permeability
Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models
Harnessing Open-Source Solutions: Insights From the FirstOpen Systems Pharmacology (OSP) Community Conference
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Meet the Team

Ingrid Michon

Principal Scientist
Consultant
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Ingrid is a medical biologist with a PhD in biopharmaceutical sciences. After several years in academia, she moved into the pharmaceutical industry, where she built over 12 years of experience in clinical pharmacology, pharmacokinetics and modeling. She also acted as the clinical pharmacology lead for regulatory submissions.
Her passion for PBPK modeling began while working as a clinical pharmacokineticist, assessing DDI liabilities in drug development pipelines. For the past 7 years, she has worked as a PBPK consultant, tackling a wide range of challenges including DDI assessment, first-in-human predictions, pediatric dosing, and regulatory submissions.

Now, at ESQlabs, Ingrid continues to advance 𝗼𝗽𝗲𝗻 𝘀𝗰𝗶𝗲𝗻𝗰𝗲 and help solve complex drug development questions using open-source tools.

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Lara Lamon

Senior Scientist
Consultant
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Lara Lamon is an Environmental Scientist with a solid drive to investigate the unknowns of chemical exposure and enhance model simulations aimed at protecting human health and the environment.

She worked at ECVAM within the JRC on the grouping and read-across of nanomaterials. Lara contribiuted to applying the read-across framework released by ECHA to support nanomaterials dossiers submissions under the REACH regulation. She further advanced this expertise in the H2020 GRACIOUS project. Additionally, she has developed and applied modeling approaches to estimate environmental emissions and concentrations of environmental and emerging pollutants, including uncertainty analysis (Monte Carlo and sensitivity analysis).

Lara obtained her Ph.D. in Environmental Science at the Ca’ Foscari University of Venice at the Environmental Chemistry and Risk Assessment Unit. During her Ph.D., she was a visiting scholar at the Safety and Environmental Technology group at ETH Zürich, where she collaborated with Martin Scheringer and Matthew Macleod at the Safety and Technology group.

Marco Siccardi

Principal Scientist
Lead Toxicology & PBPK
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Marco is a Clinical Biologist by training with a PhD in molecular pharmacology and PK/PD modelling. He spent over 15 years at the University of Liverpool working on the topic of pharmacogenetics and in developing PBPK approaches for the optimisation of drug delivery, including HIV therapy optimisation.

Marco has most recently been working with CROs in taking this approaches for modelling and simulation approaches and PKTK (Systems Toxicology) models across a number of disease areas.

Marco leads the Systems Toxicology team with the aim to promote collaborative innovation and to develop novel modeling approaches to streamline the toxicological assessment.

Mariana Guimarães

Senior Scientist
Consultant
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Mariana, a pharmacist with a Ph.D. in Biopharmaceutics. During her doctoral research, she worked on developing in vitro and in silico tools with a focus on predicting pediatric clinical outcomes. Mariana brings experience in applying physiologically based biopharmaceutics modeling (PBBM) to upport formulation development and understand oral drug absorption risks.

Before joining ESQlabs she worked at GSK in the Biopharmaceutics team, further applying tools for understanding biopharmaceutics risks in adult and pediatric drug development programs, including but not limited to the understanding of the behavior of formulations through application and development of biorelevant dissolution tests and PBBM

 

Nina Nauwelaerts

Scientist
Consultant
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Nina is a passionate scientist committed to improving the safe and effective use of medicines in vulnerable populations. She holds a Master’s degree in Drug Development from KU Leuven, Belgium and earned her PhD in the Drug Delivery and Disposition group led by Prof. Pieter Annaert, also at KU Leuven. Her doctoral research was conducted as part of the IMI project ConcePTION, where she specialized in developing and applying in vitro and physiologically based pharmacokinetic (PBPK) models to investigate medicine exposure in lactating mothers and their infants.
At ESQlabs, Nina contributes her expertise in PBPK modeling within our Toxicology/PBPK team, with a focus on special populations and advancing research in women’s health.

Sophie Fischer-Holzhausen

Scientist
Consultant
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Sophie is a biophysicist dedicated to unraveling the complex interactions underlying physiological processes through mathematical modeling and simulation. She joined ESQlabs in early 2024 as a scientist systems pharmacology.

She earned her Master’s degree in Biophysics from Humboldt University of Berlin, Germany. For her PhD, Sophie joined Prof. Susanna Röblitz’s Computational Systems Biology group at the University of Bergen, Norway, where she helped develop a mechanistic model of menstrual cycle’s endocrine regulation. Prior to joining ESQlabs, she worked as a Pharmacometrician at AstraZeneca in Gothenburg, Sweden.

Sophie is especially passionate about women’s health and leads related initiatives at ESQlabs.

Stella Fragki

Senior Scientist
Consultant
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Styliani (Stella) Fragki is a Senior Scientist in Systems Toxicology at ESQlabs, where she applies physiologically based kinetic (PBK) modeling in chemical risk assessment. Her work focuses on integrating New Approach Methodologies (NAMs) within the framework of Next-Generation Risk Assessment (NGRA), with the aim of supporting human-relevant and animal-free safety evaluations.

She is a certified European Registered Toxicologist and has been active in the field of toxicological risk assessment since 2010, supporting the (agro)chemical industry with dossier preparation for plant protection products, biocides, and REACH-regulated substances.

Stella holds a degree in Biology from Thessaloniki, Greece, and an MSc in Food Safety from Wageningen University in the Netherlands. Her PhD research focused on quantitative in vitro to in vivo extrapolation (QIVIVE) using physiologically based kinetic (PBK) modeling, integrating data from both in vitro and in silico sources. Stella is also a certified European Registered Toxicologist.

Susana Proença

Scientist
Consultant
Google Scholar

Susana Proença is a biologist and toxicologist dedicated to the leveraging in vitro and in silico data for parameterizing PBPK models and to perform chemical safety assessment. She is focused on developing frameworks and case-studies for IVIVE, extrapolation of ADME properties from in vitro to in vivo, and on QIVIVE, extrapolating in vitro effect concentrations to in vivo doses. She has experience in working with PBPK models both in OSP and in R.

Before joining ESQlabs, she worked at Wageningen University, Toxicology division under Dr. Nynke Kramer supervision. There she worked on evaluating in vitro kinetics of chemical related to different toxicological ontologies (such as cholestasis and development neurotoxicity) and developing strategies for performing QIVIVE for these chemicals. Before this she underwent an internship at ECVAM-JRC on in silico modelling of in vitro kinetics, which was followed by a stint automating chemical data curation from REACH dossiers, also in JRC.

Susana obtained her Master’s degree in Bio-Pharmaceutical Sciences from Faculty of Pharmaceutical Sciences, Lisbon University (Portugal). For her PhD thesis, she studied the in vitro kinetics in complex in vitro models and (Q)IVIVE of highly lipophilic chemicals. The thesis was supervised by Dr. Nynke Kramer at the Institute for Risk Assessment Sciences at Utrecht University. The work was multidisciplinary, envolving setting in vitro experiments, analytical methods, transcriptomics analysis and in silico modelling. Her PhD thesis will be submitted soon.