MODELING SUPPORT TO DECISION -MAKING IN DRUG R&D

Pharmacokinetic and pharmaco-dynamic modeling & simulation play a key role in throughout the drug development process, helping to generate hypotheses, interpret and understand experi-mental results and trial outcomes, to integrate available information and translate it to clinical implica-tions. Thus, modeling & simulation facilitates decision-making at each stage of drug development and helps to efficiently shape the next step.

TNO is an applied research institute with a long standing track record in applied pharmacological science, partnering with pharmaceutical and biotechnology companies worldwide to tackle specific challenges. TNO developed and applied a wide range of technologies in the field of drug research and development, including (humanized) mouse models in various disease areas, In vitro tools to study

bioavailability and DMPK, PET/CT imaging, human intervention and microtracer dosing studies. In parallel, we have developed a comprehensive PK and PD modeling and simulation portfolio ranging from physiology-based modeling, popula-tion PK-PD modeling to mechanism- based and systems approaches, which can be offered in support of other technologies or as a stand-alone service.

PHARMACOKINETIC AND PHARMACODYNAMIC MODELING & SIMULATION

Covariateanalysis

Understandingpopulationvariability

Biomarkervalidation

Biomarkeridenti�cation

Hypothesisgeneration

Targetdiscovery

Animal to humantranslation

Integratingpreclinical PK,safety, ef�cacy

Targetpopulations

Pediatrics

First in man

Trial design,simulation

Pop PK-PD

Physiologicallybased

Systemsapproaches

TNOUtrechtseweg 48P.O. Box 3603700 AJ ZeistThe Netherlands

Steven ErpelinckP +31 88 866 16 49E steven.erpelinck@tno.nl

North America (Sales Office)Tineke MeijersP +1 416 837 75 00E tmeijers@tnopharma.com

Japan (Sales Office)Kazuhiro ArigaP +81 45 478 51 30E ariga@tno.co.jp

TNO.NL

MODELING SUPPORT TO DECISION -MAKING IN DRUG R&D

PHYSIOLOGY-BASED APPROACHESPhysiologically based models such as PBPK-PD models are particularly useful for extrapolation beyond the experimental conditions. TNO has successfully employed physiologically based modeling for various translational purposes. Applications include:

In vitro-in vivo extrapolation • PK, safety and efficacy data • transporter-driven processes

Animal-to-human translational modeling

First in man; modeling support to dose selection

• integrating preclinical PK and safety data

Modeling and simulation of target populations, bridging

• e.g. pediatrics, geriatrics, obese

PHARMACOMETRICS, POPULATION PK-PDNon-compartmental, classic pharmaco-metric methods and advanced PK-PD modeling are used for statistical analysis and interpretation of (pre)clinical studies, as well as modeling support to experi-mental design:

Pre(clinical data analysis

Trial design and simulation

Statistical hypothesis testing

Understanding variability, covariate analysis

Sparse sampling design and data analysis (e.g. in pediatrics)

SYSTEMS BIOLOGY MODELING APPROACHESThe pathways involved in disease and intervention with (candidate) pharma-ceuticals are often not characterized by simple linear chains of events. TNO applies various statistical and mathematical modeling tools to create insight in these processes from a systems perspective. These tools range from mapping networks of gene expres-sion, metabolic and signaling pathways, identifying important nodes, translational biomarker models, semi-quantitative multiscale models for hypothesis generation to fully quantitative mechanis-tic PK-PD models or systems models. The choice of method or combination of methods is catered to the specific problem at hand.

The goal is not to describe a system in its full complexity, but to distill those processes that are necessary to under-stand the relationship between exposure and effect. Such a systems approach may provide critical insights to anticipate each next step of drug discovery and development:

Modeling support to target discovery and candidate selection

Hypothesis generation and study design

In vitro -to-in vivo and animal-to-human translation and validation of biomarkers for efficacy and safety

Understanding variability in or lack of treatment response

TNO’S PHARMACEUTICAL R&D AREAS OF EXPERTISETNO has broad experience in develop-ment and application of drug R&D technologies. Our modeling and simula-tion experts cooperate on a daily basis with scientists covering various areas of expertise:

Translational preclinical disease models

In vitro DMPK

Clinical studies, microtracer dosing

Omics and systems biology

(Biomarker) analytics

PET/SPECT-CT imaging

Statistics and cheminformatics

Besides our in house applied research programs, TNO participates in public-private partnerships with numerous pharmaceutical, biotechnology, nutraceu-tical, analytical and diagnostic compa-nies, clinicians and patient organisations, and in larger consortia such as IMI, NIH and EU Framework programs. In addition to scientific excellence and a good understanding of the drug development process, TNO’s scientists possess distinguished operational skills and are equipped to deliver top-level scientific evidence in a professional and efficient manner.

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