Drug Discovery Today  Volume 00, Number 00  July 2013

REVIEWS

Model-based drug discovery: implementation and impact

Sandra A.G. Visser1, Malin Aurell2, Rhys D.O. Jones3, Virna J.A. Schuck4, Ann-Charlotte Egnell5, Sheila A. Peters6, Lena Brynne7, James W.T. Yates3, fmark5, Beesan Tan4, Marie Cooke8, Simon T. Barry9, Rasmus Jansson-Lo Andrew Hughes10 and Ulf Bredberg11
1 2

derta Global Drug Metabolism and Pharmacokinetics, Innovative Medicines, AstraZeneca, So lje, Sweden lndal, Sweden Personalized Healthcare & Biomarkers, AstraZeneca, Mo 3 Modeling and Simulation, Oncology Innovative Medicines, AstraZeneca, Alderley Park, UK 4 Modeling and Simulation, Infection innovative Medicine, AstraZeneca, Waltham, MA, USA 5 lndal, Sweden Modeling and Simulation, Cardiovascular and Metabolic Disease Innovative Medicines, AstraZeneca, Mo 6 lndal, Sweden Modeling and Simulation, Respiratory, Inammation & Autoimmunity, Innovative Medicines, AstraZeneca, Mo 7 derta Translational Science, Central Nervous System and Pain Innovative Medicines, AstraZeneca, So lje, Sweden 8 Research and Discovery Informatics, AstraZeneca, Alderley Park, UK 9 Bioscience Oncology Innovative Medicines, AstraZeneca, Alderley Park, UK 10 Global Medicines Development Oncology, Alderley Park, UK 11 lndal, Sweden Drug Metabolism and Pharmacokinetics Cardiovascular and Metabolic Disease Innovative Medicines, AstraZeneca, Mo

Model-based drug discovery (MBDDx) aims to build and continuously improve the quantitative understanding of the relation between drug exposure (target engagement) efcacy and safety, to support target validation; to dene compound property criteria for lead optimization and safety margins; to set the starting dose; and to predict human dose and scheduling for clinical candidates alone, or in combination with other medicines. AstraZeneca has systematically implemented MBDDx within all drug discovery programs, with a focused investment to build a preclinical modeling and simulation capability and an in vivo information platform and architecture, the implementation, impact and learning of which are discussed here. Introduction
It is well established that the drug industry faces an enormous challenge in the form of late-stage compound attrition [13]. Some 70% of recent failures in Phases 2 and 3 of drug development, which are associated with the most signicant costs, have been attributed to efcacy or safety reasons [4,5]. A detailed review by Pzer into the root causes of this problem, demonstrated a link between a higher probability of success in Phase 2 and having an integrated quantitative understanding of the fundamental pharmacokineticpharmacodynamic (PKPD) principles, namely exposure at the site of action, target binding and expression of
Corresponding author:. Bredberg, U. (Ulf.Bredberg@astrazeneca.com), (sandra.visser@merck.com)

functional pharmacological activity at the site of action [6]. Similar results were obtained within AstraZeneca in a comprehensive longitudinal review of company projects between 2005 and 2010 (unpublished results). These ndings advocate a systematic application of PKPD principles, also known as quantitative pharmacology, throughout the drug discovery and development value chain, and to select candidates with more condence that they will be able to demonstrate the biological and translational hypothesis in clinical development. This premise should shift compound attrition to discovery or to the earlier clinical stages of development by ensuring more robustly designed studies delivering against go/no go criteria. The value of a model-based approach during drug development for improved efciency and decision-making has long been recogwww.drugdiscoverytoday.com

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DRUDIS-1186; No of Pages 12 REVIEWS Drug Discovery Today  Volume 00, Number 00  July 2013

nized [712]. However, it is only in recent years that the application of quantitative principles to early clinical and preclinical development phases has been demonstrated in the literature [1315]. Additionally, regulatory agencies are increasingly advocating the need for model-based approaches during late-stage [16 18] and early-stage development [3,19] for informed decisionmaking and optimizing trial design. Despite these advances, case studies on the application of model-based principles in the preclinical phase have been mainly conned to supporting academic research and little evidence exists for how companies have systematically implemented a model-based approach into drug discovery [2024]. Recently, AstraZeneca has taken a strategic initiative to promote the use of quantitative methods within drug projects at all stages. In this initiative, a specic cross-functional global workstream was formed with a focus on the preclinical stage. This workstream laid out a MBDDx approach that aimed to: (i) embed and implement the systematic application of quantitative pharmacology to drug discovery from target validation, via candidate selection, to proof of mechanism and concept; (ii) build a dedicated and state-of-the-art preclinical modeling and simulation (M&S) capability; and (iii) enable rapid access to cross-functional data and knowledge at the individual animal and observation level (Fig. 1). A US$13 million investment for a 3-year plan was approved to build the preclinical modeling capability through a combination of retraining, recruitment and establishment of strategic external collaborations, as well as the development of an in vivo data information platform. A successful implementation of MBDDx can support: (i) target validation and the elucidation of the biological hypothesis; (ii)

optimization of experimental design and denition of compound property criteria for lead optimization; (iii) the dening of safety margins and setting the starting dose; and (iv) predicting human dose, optimal dosing schedule and clinical study design either alone or in combination with other medicines. Once embedded and implemented into drug discovery, MBDDx can underpin key investment decisions in drug discovery in the same way that Model-based drug development (MBDD) approaches support clinical decisions. MBDDx provides a paradigm to integrate preclinical information to back translate clinical results to conrm and rene the biological hypothesis and, thus, inuence future experiments in discovery and development. With this in mind, MBDDx should not be regarded as a stand-alone activity, but should be seen as an essential prerequisite to MBDD, with a particular emphasis on building dedicated resources and multidisciplinary delivery within drug discovery. By taking this holistic approach, portfolios should benet from having a better understanding of the probability of success of a drug project and being able to identify more easily high-risk projects earlier. Portfolio and project leaders can in turn focus appropriate resources on frontloading experiments to mitigate risk. In the following sections, we describe the MBDDx approach and the lessons learnt during the implementation and operational phases. We also highlight the importance of having access to dedicated, disease area-focused state-of-the-art preclinical M&S capability, and the development of a preclinical information platform enabling rapid access to cross-functional data and knowledge. Finally, we provide case studies exemplifying the impact of the MBDDx approach on decision-making in drug discovery.

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Implementation phase Quantitative ntitative pharmacology strategy s ra st ategy te egy y

Leadership ship & governance engagement Ownership & project operating model Awareness workshops & activities Key performance indicator definitions Progress

Business as usual

Impact

Pull from governance and project Refinement of operating model Sharing impact case studies Progress

Rational governance and investment decision making Clear ownership and accountability Increased awareness, cultural change, best practice Demonstration of impact to business

Capability build
Recruitment M&S capability Training and reskilling Talent management, succession planning Advanced training Build and retention of key capability and talent Development of capability New methodology / Models / Future capability Flexibility in resourcing, state of the art methodologies

External academic collaborations and translational biomarker and PKPD Science Postdoc programs Strategic externalization activities

Information platform p at pl atfo fo orm m

Development in vivo data contract and user requirements Technical delivery of in vivo data store and query tool Data ramp-up and user acceptance training Pilot results & learning Maintenance data contract Development of integration services Routine upload of all in vivo data Early stage clinical data pilots Global standards for bench scientist and end-user Globally wide In vivo data base and exploitation tool All data accessible for full exploitation and acceptance Understanding blockers and investment areas

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FIG. 1

Model-based drug discovery (MBDDx) aims at: (i) a systematic application of quantitative pharmacology to the drug discovery portfolio from target validation, via candidate selection, to proof of mechanism and concept; (ii) building dedicated and state-of-the-art preclinical modeling and simulation (M&S) capability; and (iii) enabling rapid access to cross-functional data and knowledge at the individual animal and observation level. Focus and activities were different during the implementation phase and business as usual. The variety of impacts of the various activities is listed. Abbreviation: PKPD, pharmacokineticspharmacodynamics. 2
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Quantitative pharmacology strategy in drug discovery

The decision to initiate drug discovery activities around a specic pharmacological target is based on a hypothesis linking the pharmacological target to the disease in question. Crucial relations involved in the cascade of events from target modulation to disease modication need to be established to provide a platform of biological evidence that develops in line with the expectations of each phase of investment. Ultimately, the aim is to select a compound with the right properties for clinical development, and a clear view on the optimal doses and dose scheduling required for testing the hypothesis in the clinical setting. This demands a quantitative PKPD understanding of the link between the dose, systemic and local drug exposure and the effect on the disease, including the key intermediate steps involved in the biochemical and physiological processes (Box 1). The PK of the compound and its interaction with the target (target afnity and intrinsic efcacy) are compound-specic properties, whereas the biochemical and physiological processes downstream of the target are, by denition, compound independent and determined by the biological attributes of the system [25,26]. Robust and meaningful biomarker data, either proximal biomarkers (reecting direct target modulation) or distal biomarkers (reecting pathway or disease modication), are essential when building this quantitative insight [2729]. A conceptual framework for biomarker classication has been adopted to create a common terminology within AstraZeneca (Box 1, adapted from [27]). Fig. 1 (Box 1) is a schematic and simplied way of illustrating the biological hypothesis. The circles illustrate the different types of biomarkers (Type 16) and the yellow arrows represent the quantitative relations between the various biomarkers and between species. Using this nomenclature, MBDDx aims to create a quantitative understanding between: (i) drug exposure (Type 1) and target engagement (proof of mechanism, Type 2, 3 and/or 4); and (ii) between target engagement and effect on pathophysiology (proof of principle and/or concept, Type 5 and/or 6) in animals and its extrapolation to humans. The anticipated therapeutic concentration in the right patient population (Type 0) and associated dose and schedule could be predicted when this information is integrated with translational knowledge (e.g., target expression, potency at the target and the relative importance of the target in the disease). For safety measures, a similar approach can be applied, enabling full integration of data to estimate safety margins and therapeutic index. A common biomarker nomenclature facilitates the discussion between scientists from different functions when dening the translational biomarker and quantitative M&S strategy for preclinical activities as well as clinical proof of mechanism and proof of principle and/ or concept studies. It also aids the visualization of the knowledge gaps, leading to strategic investment in biomarkers, techniques and modeling activities. In addition, it can provide greater transparency at a portfolio level for what is known and can be measured against the biological hypothesis, thereby facilitating a more consistent risk assessment across projects underpinning portfolio and investment decisions. In Box 1, general aspirations and guidance for different phases of a project, from target validation, lead generation and optimization, to candidate selection, are summarized. Along this value chain, the knowledge base is continuously expanding via a learnand-conrm paradigm, where integration of high-quality M&S

support and biological data is essential to frame and answer the right questions and articulate the key assumptions in the biological hypothesis [30,31]. Doing the right experiments is an essential facet of MBDDx and, therefore, it is important that all experiments are preceded with in silico simulations, based on the current knowledge, to ensure an optimal experimental design. Experimental data will subsequently conrm, rene or change the biological hypothesis and quantitative understanding. First-inclass targets without clinical precedence will carry risk until clinical testing, with respect to how translatable the biological hypothesis is and how appropriate the biomarkers being measured are. Nevertheless, it is still important to ensure that sufcient (and possibly substantial) investment is made to build assays to characterize the drug- and system-specic properties to elucidate the biological hypothesis and build a quantitative understanding to predict the dose, schedule and therapeutic index. Conversely, for targets that have already been tested in the clinic, a wealth of information about system properties, biomarker behavior and translatability obtained with comparators might be available that should be utilized, to improve the condence in the dose and schedule predictions. MBDDx can be applied to all phases of drug discovery; development of a quantitative understanding of the target engagement and disease biomarkers in addition to appropriate experimental designs that take into account random or systematic variability in the biomarkers, potential temporal and doseresponse relations, and appropriate induction of disease are important aspects to take into consideration [3235]. Without studying these characteristics sufciently, and/or if studies are poorly designed, experiments are likely to produce inconclusive data or misleading conclusions. Thus, without these fundamentals in place, a project can carry substantial risk, and might lead to a lower probability of success, or require additional time and money to address later in the clinic. With upfront investment in dening the systems characteristics of the biomarker model, the experimental design can be optimized towards the (lean) characterization of drug-specic properties and, thus, improve the efciency of the lead generation and optimization screening cascade. Additionally, integration and (re-)use of all sources of data is a crucial component of the quantitative model; for example, the back-translation of available clinical data or deriving in vitro and/or in vivo preclinical data on reference or competitor compounds aiming for the same indication. Any additional information on interspecies differences with regards to the target should be integrated and conrmed to increase condence in translation. Depending on therapeutic areas, there are different challenges and opportunities in the application of MBDDx. In current neuroscience research, many drug discovery projects are rst in class, with limited or no availability of translational disease models, such as Alzheimers disease and chronic pain. Progression of compounds in these areas can carry high risk. For infectious diseases, the target engagement markers are, strictly speaking, not measured in humans, but in the bacteria or virus. This makes it even more important to have a measure for target site exposure, to ensure that target engagement with bacteria or virus can be met in the appropriate tissue. In oncology, the comparison to standard of care, irrespective of the mechanism of action, is important regardless of whether the compound in development is to be applied
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BOX 1

The quantitative pharmacology strategy uses a common nomenclature for biomarker classification
Understanding the relation between drug dose and outcome requires understanding of the PKPD of the drug. These principles can be regarded as a causal chain of events from drug dosing, distribution to the target site and elimination from the body, subsequent binding and modulation of the target related to an effect on disease and pathophysiology, measured as clinical outcome (Figure Ia). MBDDx advocates the use of a common nomenclature according to the biomarker classification system (adapted from [27], Figure Ib). Figure Ib mirrors in a simplified way the biological hypothesis implied and the circles illustrate the different type of biomarkers (Type 16). The yellow arrows represent the quantitative relation between the biomarkers and species. This includes both equilibrium relations as well as
(a)

temporal aspects (e.g., a time delay between PK and the measured biomarker). In drug discovery projects, these mathematical relations need not connect every step in the process, but can quantify, for example, Type 1 in relation to Type 3 biomarkers. In this nomenclature, PoM markers are those that define the degree and duration of target engagement sufficient for viable hypothesis testing (Type 2, 3 and/or 4). PoP markers are those that measure beneficial effect on targeted disease process or pathophysiology (Type 5), whereas PoC markers are Type 6 and/or Type 5. Type 0 markers reflect patient stratification markers for personalized health care (PHC). Generic quantitative pharmacology aspirations and criteria at different stages in drug discovery for the quantitative characterization of these biomarkers are listed in Figure Ic.

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PHARMACOKINETICS
Compound-specific properties Dose
Cp
Plasma
k

PHARMACODYNAMICS
System-specific properties
Target mechanism Disease process Pathophysiology

Ce
Target site

k k

Target occupancy

Outcome

Target exposure

Target engagement

Transduction to efficacy and/or Safety

Type 0

(b) Animal

Type 4B
Physiological response

Quantitative relation between biomarkers Interspecies translational relation

Biomarker that determines the disease state or the potential for therapeutic response or patient stratification (e.g., genotype or phenotype) The PK of the compound; typically unbound plasma concentrations and/or target site exposure Target occupancy via a direct measurement of receptor binding.(e.g., PET, autoradiography) An immediate biochemical response as a result of the interaction with the target (e.g., measure of signal transduction or of an enzyme product) A physiological or tissue response directly linked to the pathophysiology Parallel pharmacology driven through the same target but not directly linked to the pathophysiology (e.g., different tissues, such as central versus peripheral) A biomarker of the pathophysiology (e.g. disease marker) Clinical measure of the outcome in a patient population approved by regulators (e.g., pain relief)

Type 1 Type 1
Drug concentration

Type 0
Genotype/ phenotype

Type 2
Target occupancy

Type 3
Target mechanism

Type 4A
Physiological response

Type 5
Pathophysiology or disease process

Type 6
Outcome

Type 2

Type 3

Type 0
Genotype phenotype

Type 1
Drug concentration

Type 2
Target occupancy

Type 3
Target mechanism

Type 4A
Physiological response

Type 5
Pathophysiology or disease process

Type 6
Outcome

Type 4A Type 4B

Human

Type 4B
Physiological response

Type 5 Type 6

PHC

PoM

PoP

PoC

(c)

Generic MBDDx aspirations and criteria for drug discovery phases Target validation (TV) Lead generation (LG) Lead optimization (LO) and candidate selection
Clinical candidate criteria should be defined at start of LO based on quantitative PKPD relations established during LG Refinement of key relations with higher quality compounds Target engagement PKPD as a driver for compound optimization For clinical candidate compound: estimate therapeutic concentration time profile based on the PKPD relation developed in preclinical species, and translation knowledge, such as differences in PK, target potency and system properties Integration of PKPD for safety parameters to assess safety margin Translational plan outlining development and Evaluation and selection of appropriate target evaluation of appropriate biomarkers to engagement biomarker (Type 2, 3 or 4) and build PKPD understanding optimization of PKPD study design If in vivo target validation model and a Use reference or lead compounds and target reference compound are available, apply engagement biomarker to establish relation PKPD principles to study design and ensure between in vivo and in vitro potency a sufficient duration and level of systemic Establish the level of target engagement unbound exposure relative to the in vitro required for meaningful efficacy on the disease potency while considering target class (Type 5) biomarker

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FIGURE I

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Capability build
To deliver the MBDDx strategy, an overall modeling capability requires in-depth mathematical and computational skills as well as specialism in the application of M&S to biology and disease. At the start of this initiative, there was a clear capability and capacity gap within AstraZeneca. To address this, dedicated preclinical M&S groups were formed within each therapeutic area and were sized to support the respective portfolio. Having therapy-aligned local M&S groups has been a clear driver of success to establish strong working relations, particularly with in vivo pharmacologists and translational scientists. Alignment to the therapy areas has been important overall for driving the effectiveness and impact of MBDDx into projects. It was evident when forming these focused M&S groups, that this resource and competence was scarce within the company. To address this resource gap, a four-pronged strategy was established to build the internal capability. First, a concerted global recruitment campaign was launched to attract talent from outside AstraZeneca. Second, opportunities for accelerated development were given to individuals in the organization that did not have the formal training, or extensive experience in M&S, but had an interest in, and demonstrated an aptitude for, M&S. More experienced scientists were offered advanced training courses to increase their overall technical skills in the application of advanced modeling approaches. Third, seven collaborations were established with key academic institutions to strengthen, in the longer term, the pool of M&S scientists. Finally, ten internal scientic research positions (post-doc) were created to provide an accelerated development path for promising young PhD scientists as well as developing state-of-the-art expertise in translational biomarkers, novel quantitative models and methodology. All four elements were successful approaches in their own right, albeit collectively, building a capability of this kind is difcult and takes considerable time. For capacity increase, to build exibility in the total resource available and to access the technical skills that might not be available internally, external capability provisioned through partnerships with dedicated M&S providers was established. To maintain this capability successfully in the medium to long term, other factors such as succession planning, competitive benets, development opportunities via specializations and job rotations from other functions, will need to be addressed. Moreover, empowering inuential scientists in other functions within the organization to become MBDDx ambassadors can help advocating the importance and impact of this approach.
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Implementation phase
The development of quantitative pharmacology models with the integration of preclinical and clinical information to support decision-making requires a multidisciplinary approach and a close interdependence between several disciplines, including pharmacology, drug metabolism and PK (DMPK), translational science, safety, systems biology and pharmacometrics. Given that research and development at AstraZeneca is organizationally divided into therapeutic areas, cross-functional implementation teams for each of these therapeutic areas were established to lead tailored implementation packages and activities based on the general principles agreed in the global MBDDx workstream. The implementation phase started with engagement with the line management of senior global and therapeutic areas to obtain endorsement for the implementation plans and to agree on expected outcomes. The therapeutic area teams had an important role in the change process and served as advocates for the MBDDx strategy, creating a shared purpose within their different functions, facilitating scientic support and awareness training to projects and funneling questions and challenges back to the global team. This provided an efcient way of identifying capability gaps across the organization, and delivering more tailored awareness workshops and technical training courses. The awareness training for implementation into projects was primarily performed via engagement in face-toface workshops, where the key skill groups, project leaders and senior management were targeted. The concepts were illustrated with examples from specic therapeutic areas, and project teams were then engaged in workshops with the aim to obtain a health check on MBDDx status, gaps and plans. The generic drug project operating model and investment milestone criteria have had the quantitative pharmacology aspects embedded into them. Additionally, individual projects use a translational science and biomarker strategy document to capture the quantitative pharmacology aspects. This includes a status, gap and risk analysis and resulting plan for biomarker development and quantitative pharmacology analysis. This plan is developed from the start of a project and is regularly updated before critical investment decisions, such as lead optimization, candidate selection and during clinical development, and is used by local governance bodies in preparation for investment decisions. As a result of these efforts, best practice has been established and preclinical M&S scientists are contributing to projects in all phases. The M&S

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alone, as a replacement, or in combination with another compound. In addition, for novel target combinations, quantitative understanding provides a way to understand the respective contributions of multiple mechanisms of action at different targets, which merge in the pathway (e.g., at the target engagement or disease level, determining competition, addition or synergy of effects [36]). For respiratory diseases, the challenges are quantication of the target site distribution and limited availability of preclinical models for chronic respiratory diseases, such as chronic obstructive pulmonary disease. In the cardiovascular area, there is an opportunity to learn about the cardiovascular system behavior from both pharmacology and safety studies. For diabetes mellitus, disease and biomarker models are relatively well developed, giving the opportunity to build systematically in silico models to study targets and combinations.

scientist is responsible for dening the key M&S activities required to increase the condence in the project with respect to the biological hypothesis and the human dose predictions, and to deliver agreed activities to support quantitative elements of the preclinical project translational strategy. This has been a consistent success factor for the implementation across all therapeutic areas; each M&S scientist is an advocate and works in partnership with the DMPK scientist, pharmacologist and translational strategist to apply the MBDDx strategy to drive the project forward. Projects have generally embraced this approach and, with a strong pull from governance, this has led to an increased expectation that model-based approaches will be applied to all decisions.

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Building a data platform to enable analysis of complex in vivo studies

Efcient use of modeling requires access to diverse and highquality data sets and a exible data management infrastructure. Achieving this task in large pharmaceutical companies is challenging because the data sources and types differ among therapeutic areas and a solution that ts one area might not be completely transferable to another. Therefore, for preclinical in vivo data, a single ontology, known as the in vivo data contract, was generated from internal denitions and experimental procedures, with the idea to link the biology and endpoints across studies and therapeutic areas into common clusters. A high-level view of the approach is described in Box 2. Establishing and maintaining such a data contract had the benet of enabling integration of diverse data sets into a common platform that can be exploited at the enterprise level; providing uniform retrieval of data and

exibility to manage data without imposing on other parts of a complex work ow. Areas that required data to be expressed in a rigid way (e.g., when specifying a dose route) and areas where exibility was essential to describe the in vivo experiment appropriately (e.g., when specifying the procedural details or unique experimental details) were identied early. The implementation of the solutions via a network of informaticians has resulted in the streamlining of therapeutic area or in vivo model-specic processes for the bench scientists, automating manual steps in processing the data and signicantly improving the quality of data and metadata capture. Additional benets of improving knowledge sharing across multiple customer groups, with cross-links to other data store systems, enables the rapid recovery of data to support regulatory body inquires. Impact on user uptake and engagement and the payback to the data generators were compelling, as illustrated in Box 2.

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BOX 2

Application of company-wide in vivo data reporting standards: in vivo data contract

The in vivo data contract is a set of standards that creates a crosstherapeutic area framework for representing all in vivo data. Establishing and maintaining a data contract enables integration of different data sets (spanning different therapeutic areas) into the platform through a common understanding of data types without the need for detailed understanding of the experimental procedures, or recognition of common endpoints. This framework enables uniform retrieval of data and flexibility to manage the integration of data. The timeline view (Figure I) represents a typical in vivo study capturing the initiation of the model, dosing (acute or

chronic) and different measurements or analyses that might be made from samples taken in the course of the experiment. The timeline is not fixed; new measurements and sampling procedures can be added while the experiment is in progress. The results view (Figure I) exemplifies how the study is structured to represent different data points on each individual animal that contribute to the whole study. Analysis performed long after the termination of the experiment can be added into the data set (not shown). The benefits of implementing a single data platform are represented as direct resource savings delivered through addressing data handling and storage.

The in vivo data contract

Timeline view
Dose (anaesthetic) 09:00
Preparation 1

Preparation, induction, dose, measurement, sampling, termination etc. are all formally defined terms in the data contract Induction 1 Preparation 2 Termination Induction 2 09:30 13:00 Dose 1 TIME Sample 1 (blood) 14:00 Dose 2 Sampling 2 Sample 2 (blood) 15:00 Measurement 5 (on animal body weight) Sampling 3 Sample 3 (brain) Measurement 6 (on sample 3 brain concentration) Measurement 7 (on sample 3 biomarker concentration)

09:15

Setting up the study and the animal model (e.g., preparatory surgery, administration of challenge, e.g., to simulate a disease condition).

Sampling 1

Measurement 1 (on animal body weight) Measurement 2 (on sample 1 plasma concentration)

Measurement 3 (on animal body weight) Measurement 4 (on sample 2 plasma concentration)

Results view

Measurement
1 Body weight

Result
1 = 450 g 2 = 0.3 uM 3 = 448 g 4 = 0.4 uM 5 = 462 g 6 = 50 nmol/kg 7 = 190 nmol/kg

Resource savings of a single data platform

Working with tailored templates or tools for data handling by pharmacology and DMPK scientists to reduce manual data manipulation Addressing the automation of integration of PK, biomarkers and covariates (e.g., bodyweight) to generate standard plots Automating the flow of information and data between bioscience and DMPK improves accuracy of data transfer Exposing to data through a single platform 40 60% of data analysis time and/or study type

Sample 1 (blood)
Animal
ID = 123

2 Plasma concentration 3 Body weight

Sample 2 (blood) Sample 3 (brain)

4 Plasma concentration 5 Body weight 6 Brain concentration 7 Biomarker concentration

0.5 FTE across 5 8 drug projects

Up to 0.8 FTE per project

NB: multiple measurements on a particular sample or animal are permitted

0.4 FTE per modeler

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The main investment and challenge of this task were in the infrastructure and data load, whereas the functionality that retrieves individual animal data to enable modeling of compound exposure, inhibition of primary or target related biomarkers, efcacy and therapeutic index has been the minor task of this undertaking. The overall impact was a signicant 40% saving of the preclinical modelers time, therefore increasing the impact of modeling through drug projects in AstraZeneca. To ensure a continuum from MBDDx to MBDD and that the right learning is taken back from the clinic (back-translation), integration of preclinical and clinical data is essential. To understand the infrastructure requirements for forward- and backtranslation of emerging clinical data, an additional investment was made to pilot the integration of various clinical and preclinical data sources to form a project-centric database. This database was exploited to facilitate projects to dene and respond to key questions that are addressed in early clinical studies. These key questions concerned target engagement, safety margin and/or therapeutic windows, impact of different dose schedules, forward- and back-translation of efcacy and safety biomarkers, and benchmarking (comparator) data. In this pilot, such knowledge was extracted and visualized using an internally developed knowledge management tool. The Knowledge plot enabled full integration of preclinical and clinical, efcacy and safety data and increased the exibility in visualizing information during all development phases. This pilot clearly demonstrated that real-time forward- and back-translation had signicant impact on decisions made to project teams, by improving cross-functional work and increasing transparency of the large amount of compound and project information. This initiative also highlighted the requirements on data and infrastructure for aligning several existing translational data platforms across preclinical and clinical. It also exposed the need to develop a more enterprise solution compared with those used in the pilot projects, which were tailored to the needs of the individual project.

Project impact
To demonstrate the return on investment made by the business, the impact of adopting the MBDDx strategy into projects across the therapeutic areas was captured via a quarterly collection of case study examples. These case studies illustrate how MBDDx has helped projects avoid, or reduce, cost and increase the likelihood of technical success. These examples have been powerful in raising general awareness and demonstrating the value of applying the quantitative pharmacology strategy. Three examples are illustrated in more detail in Boxes 35. The nancial investment and, thus, potential cost savings or cost avoidance during early discovery phases might seem relatively small compared with the clinical stages, and these are usually measured only to the next discovery or development phase. However, the average preclinical costs for a successful launch is US$270 million [1] and, therefore, ensuring a higher success rate via early termination or reduced cycle time by doing the right experiments in a more optimal way, will deliver return on the capability and infrastructure investments. Also, by having a better quantitative understanding of the biological hypothesis, better quality candidates will be taken forward with more informed decisions on predicted dose and scheduling for clinical testing, and this will offer large cost avoidance and savings over a longer time frame. For example, it took 6 years of Phase 1 development of avopiridol by the US National Cancer Institute to come to a recommended schedule, because it takes 12 years and 50100 patients to get sufcient data to rule out or in a schedule. If preclinical insight and testing could reduce the number of permutations, this can lead to both a substantive cost ($10 million per tested schedule) and time (1 year) savings during early clinical development. Such a preclinical approach is illustrated in Box 3 by establishing a robust view on dose and schedule options for clinical studies. Efciency improvements in screening cascades and reduced cycle times for make-test cycles have been demonstrated through establishing in vitroin vivo correlations (see also [37]) and devel-

BOX 3

Can an intermittent, rather than continuous, dose schedule offer improved tolerability while maintaining efficacy?
The AKT signaling pathway is one of the most frequently deregulated pathways in human cancer. The AKT protein is an important node in this signaling cascade that controls cell survival and progression through the cell cycle. Hyperactivation of AKT leads to deregulation of this complex signaling cascade and this unbalance is implicated in tumorigenesis. AKT inhibitors are known to act by preventing cell proliferation and, at high concentrations, cell apoptosis. The measurement of down-stream kinases can be used as predictors of the effects of AKT inhibition [44]. To elucidate the schedule dependence of antitumor efficacy in a mouse breast cancer model (BT474c xenografted cell-line), a PKPD-efficacy model was established to relate the PK of an Akt inhibitor with the resulting biomarker dynamics (PD) on the AKT signaling pathway, specifically pS6 as a measure of cell proliferation and uGSK3b as a measure of apoptotic threshold. The PD response was then used to drive cell inhibition and cell death on a modified model of tumor growth [45].

By having a quantitative understanding of these biomarkers, which represent a measure of phenotypic responses that result in efficacy (tumor growth inhibition), the model enabled hypothesis-driven interrogation of the biology and the balance of contribution to overall efficacy from multiple mechanisms of drug action. Understanding these relationships is useful when considering different scheduling options, for instance to optimize a therapeutic tolerability margin. The complex interplay between drug exposure, target inhibition, phenotypic responses and efficacy would require a considerable number of experimental studies to find optimal dose schedule options using empirical study design strategies. By contrast, a model of this kind offers the opportunity to simulate different scheduling options and direct the experimental design to a few studies to validate the hypothesis. The additional detail encapsulated within a PKPD model provides greater confidence in extrapolating predictions to human, both in predictions before the clinic and in simulations of alternative schedules in response to the emerging tolerability profile from Phase 1 patient studies (Figure III).

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(a)
PK pGSK3 Apoptosis

Tumour volume (cm3)

% of control

Concentration

pGSK3b %Control

Increased apoptosis

pS6 %Control

Reduced proliferation

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FIGURE I

pS6 Antiproliferation

Cycling cells

Cell death

(b)
150 100 50 0 72

Biomarkers High
Tumour regression
Reduced proliferation rate Low apoptotic threshold = cell death

1.2 1 0.8 0.6 0.4 0.2 0 300

Efficacy

pS6

uGSK3

Growth inhibition
Reduced proliferation rate Low apoptotic threshold = cell death

84

96 108 Time in hours

pGSK3b pS6

120

pS6

uGSK3

Low

500 Time (h)

150 mg/kg BD

700

Control

300 mg/kg QD (4days)

(c)
100 80 60 40 20 0 100 80 60 40 20 0

Simulated biomarkers

Simulated efficacy

1 0.9 0.8 0.7 0.6 0.5 50 100 150 0.4 0.3 0.2 300 400 500 600 Time in hours 700

50 100 Time in hours

150

Continuous dosing 4 days per week 2 days per week

Drug Discovery Today

example of modeling and simulation in oncology: dening efcacious schedules. (a) Schematic of the pharmacokineticpharmacodynamic (PKPD) efcacy model where two biomarkers are used to drive two effects in the tumor growth model. (b) The model was parameterized using experimental PD (left panel) and tumor growth data (right panel). (c) The model was simulated to identify the equi-efcacious regimen to dene clinical dose scheduling options to balance efcacy and tolerability.

opment of calculation tools. An example of improved efciency and improved decision-making is illustrated in Box 4, where a minimalistic single time-point safety PD study could be used to predict a longer-term preclinical safety endpoint. The estimated in vivo potencies in the safety and efcacy disease model enabled quantication of the safety window, which facilitated the governance decision to invest in the lead optimizing phase. The disease model efcacy also correlated well with in vitro potency, enabling a priori estimate of the level of separation between efcacy and
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safety based on a relatively cheap and quick turnaround screening cascade. Other examples have demonstrated that, in the case of good quantitative understanding of the relation between in vitro and in vivo potency, characterization and optimization could be done primarily on in vitro data, whereas only the most promising candidate would be tested in vivo to conrm the prediction. This has led to reduced need for costly and time-consuming in vivo experimentation and more rapid progression of the project

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BOX 4

Lead optimization investment decision based on quantitative understanding of efficacy and safety within diabetes mellitus and diabetic complications
It is known from clinical studies that antagonism of a particular target can delay disease progression, but that it is associated with an undesired effect, limiting the use of currently available antagonists. The project team aimed to develop a compound with minimal undesired effect while retaining efficacy. Safety system parameters were derived by applying a pool precursor model to describe an acute, short term safety pharmacological study with a time-resolved Type 3 biomarker responding to varying provocation routines of an endogenous agonist in the presence of a competing antagonist (compound A). This model was then used to estimate in vivo safety biomarker inhibitory concentration 50 (IC50) for compounds AF, by incorporating their PK profiles and using a minimalistic single PD time point sampling study (Figure Ia). The IC50s derived in this manner were devoid of confounding PK or study design differences and correlated well on a ranking level to safety Type 4 biomarkers in longer term studies (data not shown). In vivo efficacy disease progression biomarker (Type 5)
(a)

data were then modeled by a linear disease progression model and in vivo efficacy IC50s were obtained for compounds AF (Figure Ib). In vivo efficacy IC50s were also well correlated to in vitro IC50s (not shown). The ratio of in vivo safety to efficacy IC50 was used as a quantitative measure of separation between efficacy and safety (Figure Ic). The resulting varying range of ratios supports the hypothesis that separation between target-mediated efficacy and safety is possible (compounds D and F). Interspecies translatability of the preclinical disease progression model was confirmed by measured clinical and preclinical efficacy of a clinical tool compound using the same biomarker in all species and comparing this to the predicted daily receptor occupancy, based on in vitro IC50 data (Figure Id). This example demonstrates that applying a MBDDx approach gave quantitative evidence that separation between efficacy and safety could be obtained for this target, and suggests interspecies translatability of efficacy. These two factors were key determinants for the lead optimization decisions and for driving this project forward. The results also informed subsequent in vivo study designs to ensure that these were quantitative and conclusive.

Preclinical safety PKPD model

Pool/precursor PKPD model with competitive interaction
PK Compound: antagonist ka Drug Dose conc Dose kin Endogenous Agonist: ktol + System Vehicle injection kin Pool kout Response kout rate PD ka Cp m kout ktol Cl 0.8 Response

(b) Preclinical efficacy PKPD model

Linear disease progression PKPD model
ka Dose Drug conc Cl

Example of model fit for PD using fixed system parameters

Antagonist dose Vehicle 0.8 0.1 mg/kg

Example of model fit for PD

5

0 2 4 6 10 mg/kg

0 2 4 1 mg/kg 0.8 0.8

Drug function: Imax- model

Disease Biomarker

PK

Drug function Competitive interaction 0 0 0 2 4 6 0 2 4 6 Time (h) O Experimental values Model fit

Safety in vivo IC50 (Type 3BM)

PD Progression rate

0.05
PD (Type 5)

0 200 400 600 800 Time (hrs) O Vehicle O Treatment Model fit Model fit

Efficacy In vivo IC50 (Type 5 BM)

Main assumption: -antagonist can fully block the disease progression (demonstrated by a compound)

(c)

Preclinical difference between efficacy (Type 5BM) and safety (Type 3BM) IC50s

(d) Response (% fold of placebo/vehicle)

100 80 60 40 20 0

Preclinical and clinical efficacy with clinical tool

Compound A clinical tool B C D E F

Separation: Safety / Efficacy in vivo IC50 1.2 0.4 0.3 9 0.3 20

Human Mouse Rat

20

40

60

80 100

Predicted daily receptor occupancy (%) from in vitro IC50

Drug Discovery Today

FIGURE I

[37,38]. Box 5 provides an example of an early termination of a lead series by applying quantitative modeling, which enabled governance and the project team to come to a rational and informed decision. Other signicant efciency improvements have been demonstrated by the design and implementation of

software libraries to support routine model simulations, parameter estimations, reading and writing PK and PD data from/to Excel, and writing presentations to PowerPoint, as well as automated human dose predictions. With data platforms that expose data on an animal level and experiments that are more sophisticated and
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BOX 5

Early termination of project via integration of in vitro, in vivo efficacy and safety
A bacterial dynamics model was developed to describe the killing kinetics of selected compounds against Pseudomonas aeruginosa. Using a population modeling approach, the model was fitted simultaneously to the in vitro time-kill results obtained at seven concentration levels, ranging from 0 to 16-fold [the minimum inhibitory concentration (MIC)]. The model and its parameter estimates were then linked to the mouse lung PK model developed for the same compound, and the combined PKPD model was used to predict the in vivo time course of response in a immunecompromised mouse lung model. The population modeling approach described the in vitro data well and was also able to predict the in vivo data, hence confirming the PKPD in vitroin vivo correlation (IVIVC, Figure Ia). Simulations of in vivo response were then conducted for multiple dose and regimens (Figure Ib). The dosing regimen required to achieve stasis (no net bacterial growth from baseline) at 24 h in the immune-compromised mouse model was determined to be 700 mg/kg every 2 h for 4 doses (a total dose
(a)
Bacterial load (log10(CFU/mL)) 10 8 6 4 2
0x MIC 0.5x MIC 1x MIC 2x MIC 4x MIC X 8x MIC 16x MIC

of 2800 mg/kg/day). This high and frequent dosing regimen was deemed not achievable based on the mouse tolerability data and the physicochemical properties of the compound. Through M&S, it was demonstrated that (i) the in vitro time-kill data can be utilized to predict the in vivo time course of the selected compound in a mouse infection model; and ii) high doses would be required to achieve in vivo efficacy, which were not feasible from a formulation perspective. In addition, the results demonstrated that the exposures required for efficacy were exceeding concentrations in a safety study that demonstrated adverse effects. The results, together with the mouse tolerability and physicochemical data, suggested difficulty in progressing with this chemical series for the program. This example demonstrates the potential utilities of modeling the in vitro time-kill data in infection and establishing the PKPD IVIVC early on for infection programs. The prediction of efficacious dose and feasibility of dosing avoided the use of resources and animals. The same modeling approach could be applied to other compounds and series to predict in vivo efficacy based on in vitro data before having any in vivo efficacy data.

Bacterial load (log10(CFU/lung))

Free lung conc. (mg/L)

Bacterial load (log10(CFU/lung))

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Observations
50 mg/kg/day

Simulations
100 mg/kg/day 150 mg/kg/day

10 8 6 4 2 0 8 16 24 0 8 16 24 Time (Hours) 0 8 16 24

8 16 Time (Hours)

24

(b)
2.5 2.0 1.5 1.0 0.5 0.0

2800 mg/kg/day

3200 mg/kg/day

3600 mg/kg/day

4000 mg/kg/day

4x MIC

2x MIC

5.5 4.5 3.5 2.5

Stasis 1 log kill

16

24

16 24 0 8 Time (Hours)

16

24

16

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FIGURE I

A bacterial dynamics model to describe the killing kinetics of selected compound against Pseudomonas aeruginosa. (a) In vitroin vivo correlation: a population modeling approach was used to describe the in vitro bacteria kill, which was then linked to a pharmacokinetic (PK) model for lung exposure and used to describe the in vivo response of different doses in a mouse infection model. Symbols are the observations and lines are model predictions for in vitro time-kill (left panel) and in vivo time course data (right panel). (b) Simulated lung PK prole (top panel) and bacterial effect (lower panel) for 700 mg/kg to 1000 mg/kg dosed every 2 h for 4 doses. The dosing regimen required to achieve stasis (no net bacterial growth from baseline) at 24 h in the immune-compromised mouse model was determined to be 700 mg/kg every 2 h for 4 doses (or 2800 mg/kg/day).

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well designed, there were numerous of applications of advanced modeling techniques, such as population methods and metaanalyses, to explore fully understanding of the system properties in animal and humans and the variability used for extrapolation purposes [3943].

Concluding remarks
Over the past couple of years, AstraZeneca has moved from a situation where preclinical quantitative approaches were applied consistently in very few projects, to a situation where it is consistently deployed across most projects in the portfolio, accompanied by strong support from governance bodies. This has signicantly impacted the condence in decision-making based upon MBDDx knowledge for early termination of compounds, more efcient and focused lead optimization programs, and quick and efcient progression of the most promising candidates. Key factors for MBDDx success have been the local integration of M&S to address the specic therapy area needs and challenges, which also helped dene shared purpose and goals for the constituent

Acknowledgements
The authors like to acknowledge the late Thierry Groblewski, and thank many other colleagues with current or previous afliation with AstraZeneca for their invaluable contributions to the MBDDx workstream activities. These include Corinne Reimer, John Clapham, Pete Webborn, Ulf Eriksson, Gemma Satterthwaite, Corinna Fletcher, James Hinchcliffe, Scott Thomas, Tim Piser, Johan Gabrielsson and Hugues Dolgos.

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functions of MBDDx, namely pharmacology, translational science, safety and DMPK. Further success factors have been the desire from project teams, governance and senior management to utilize MBDDx in decision-making. In addition, the development of a company-wide preclinical information platform has been a pivotal factor in success. Important next steps are the further integration with computational biology and clinical pharmacometrics (i.e. quantitative and systems pharmacology [47]) building towards a more efcient modeling continuum to drive effective business decisions.

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