Session I: Accurate Lead Selection; Session II: Acceleration of Preclinical Studies; Session III: Acceleration of Clinical Studies

Planning Committee/Program Chairs

Dr. Subrahmanyam Vangala, RW Johnson PRI

Dr. Albert P. Li, Phase 1 Molecular Toxicology, Inc.

Dr. Rakesh Dixit, Merck Laboratories

Dr. Alan G.E. Wilson, Pharmacia

Dr. Dale Johnson, Eos Biotechnology

Dr. Yuichi Sugiyama, University of Tokyo

Monday, December 2, 2002

Session I: Accurate Lead Selection

8:00 AM – 9:00 AM – CONTINENTAL BREAKFAST and REGISTRATION

8:00 AM – 5:00 PM – EXHIBITS

A. Virtual Screening

(Chairs: Alan G. E. Wilson and Dale Johnson)

9:00 AM – 9:45 AM Keynote Speaker

Speeding Innovation: A Look at the Evolving Roles and Strategies from Preclinical to Clinical Development (Peter Smith, Millenium Pharmaceuticals, Inc., Cambridge, MA) With the expanding costs of discovering and developing highly effective and safe new products for unmet medical needs, companies are struggling to find more effective ways to identify lead molecules, which have a high likelihood of success including finding ways that are faster, and require fewer resources overall. Through a combination of operational excellence and strategic approaches, expedited drug development is becoming a reality. Much of this change has been incremental, but through the application of new technologies, greater success is expected. Through reengineering, many companies have discovered new processes, which have reduced cycle times and improved efficiency. The idea of “functional siloism,” where cross-discipline communication was previously rare, is disappearing and there is better integration and alignment across disciplines. The technology piece is presently a big promise with high expectations. Ideally, high throughput approaches to identify the chemical attributes for effective receptor or enzyme targeting are combined with novel animal models (i.e., transgenics, knockouts, etc.) to give even more accurate readouts for human efficacy. This will allow us to link pharmacology to early clinical development better, where biomarkers and/or surrogates of human efficacy in early to mid phase clinical trials will be critical for enhanced speed and decision making. Overall, the aim is to reduce significantly the attrition rate, and improve accuracy in compound selection leading to less time a compound spends in the preclinical development phase. This promising new technology includes genomics, metabolomics, transgenics and in silico approaches. Through a combination of these approaches with innovations from the clinic such as novel patient selection and trial simulation strategies and productivity enhancements, the pace from preclinical to clinical development is expected to accelerate. The “gene to patient” concept is becoming a reality, and with enhanced productivity, the process of drug discovery and development will undoubtedly improve in the new millennium.

9:45 AM - 10:30 PM

Integration of Predictive ADME and Toxicity Modeling into High Throughput Screening to Support Drug Discovery (Alan G. E. Wilson, Pharmacia, St. Louis, MO)

Toxicity and pharmacokinetic issues remain a significant cause of new drug candidate failures. This has increased the need to have early screens for physiochemical, ADME/PK and toxicity properties. An increasingly important component of this screening paradigm is the use of computer–based predictive models (in silico). Global and local (quantitative and qualitative) models are being applied to library design, to help prioritize synthetic programs, and to identify structural features which may contribute to undesired effects. In addition, searchable databases and database engines are marketed for data storage and retrieval. Predictive modeling, in conjunction with other screening technologies, has the potential to transform our drug discovery paradigm. This presentation will discuss the current status of in silico systems for ADME and toxicity prediction, present examples of the utility in drug discovery and discuss integration with other screening technologies.

10:30 AM – 10:45 AM - BREAK

10:45 AM - 11:30 AM

New Approaches for Predictive Toxicology (Dale Johnson, Eos Biotechnology; S. San Francisco, CA) New approaches using in vitro systems coupled with gene expression data are being developed to create predictive models of human toxicity. Selection of the appropriate experimental design with adequate controls is critical in moving towards a higher throughput screening system where both chemistry and biological endpoints can be evaluated. A case study on developing such a system will be presented.

B. Biological Screening for Human Drug Properties

(Chairs: Albert P. Li and Subrahmanyam Vangala)

11:30 AM – 12:15 PM

A Critical Evaluation of the Use of In Vitro Human Liver Systems in the Prediction of Human Drug Metabolism, Drug Toxicity, and Drug-Drug Interaction Potential (Albert P. Li; Phase 1 Molecular Toxicology, Inc.; Santa Fe, NM) In the past 5 years, there has been an explosion in the use of human-based in vitro system for the prediction of human drug properties. Tremendous progress has been made in drug metabolism, drug-drug interactions, and mechanistic toxicology. In this presentation, the most common in vitro systems: Caco-2 cells, liver microsomes, hepatocytes, liver slices, will be critically reviewed both in their strength and weaknesses. A recommendation will be made one the best combination of in vitro experimental systems for the prediction of human drug metabolic fate and clearance, drug-drug interaction potential, and drug toxicity.

12:15 PM – 1:30 PM – LUNCH

1:30 PM - 2:15 PM ***NEW SPEAKER****

Toxicity Ranking and SAR based on High Throughput Screening in a Human Hepatocyte Cell Line (Norman L. Sussman; Amphioxus Cell Technologies, Houston, TX) The process of turning a lead into a drug requires multiple rounds of rank ordering and resynthesis to strike an optimum balance between activity on the one hand, and drug-like properties on the other. This process of drug development is best achieved early in the course of development when relatively few resources have been expended and no lives endangered. Drug development has been aided by fast, cheap, and relevant in vitro assay systems so that predictive software, recombinant enzymes, mechanization, and absorption modeling are all in routine use. We address the area of human toxicity. Using a highly defined, metabolically active human liver cell line coupled with a suite of physiologically relevant assays, we are able to identify toxicity, CYP induction, and MDR activity, and distinguish between safe drugs and their toxic analogues. The reproducibility and predictive power of the system will be demonstrated using several well known examples of withdrawn compounds compared to analogues that are still on the market, and the feasibility of structure-based toxicity modelling will be discussed.

2:15 PM - 3:00 PM

A critical evaluation of in vitro toxicology/metabolism tests used for prioritizing novel therapeutic agents and a proposal for a new approach (Sylvia Zhao; Hoffmann-La Roche; Nutley, NJ and Peter J. O’Brien; University of Toronto; Toronto, Ontario CANADA) Current tests used for prioritizing new drugs at the discovery and development stage will be critically reviewed .New high throughput in vitro techniques for screening agents for pro-oxidant radical formation and oxidative stress induction will also be proposed. The use of cytochrome P450 inhibition/induction and covalent binding of NCEs as biomarkers for predicting drug-drug interaction potential and evaluating drug candidate safety will also be critically reviewed and novel biomarkers will be proposed.

3:00 PM – 3:15 PM – BREAK

3:15 PM - 4:00 PM

Bridging the Gap Between Drug Discovery and Development: ADMET Properties, Mechanistic Studies and Biomarkers (Vangala Subrahmanyam, RW Johnson PRI, Raritan, NJ) ADMET properties play a critical role in the disposition, safety and efficacy of drugs. Understanding these processes and predicting human ADMET properties of drugs has been a challenge before moving them into the clinic. From the past experiences it is clear that either in vitro (animal and human) studies alone or in vivo (animal) studies alone cannot predict human ADMET properties of a drug. It appears that a combination of several in vitro and in vivo models are required with special emphasis on conducting mechanistic studies to discover “novel biomarkers” to help move compounds into clinic at much higher rate.

4:00 PM - 4:45 PM

Accurate Lead Selection: Biological Screening for Human Drug Properties (Peter Bullock, Purdue Pharma, LP; Ardsley, NY) Relatively recent advances in engineering and biology have facilitated the evaluation of the pharmaceutical properties of lead compounds. These properties often contribute to the success or failure of development candidates in pre-clinical studies by way of their influence on pharmacokinetic behavior. It is now possible to differentiate between lead compounds by characterizing these drug-like properties in vitro. Individual assays are available to investigate factors affecting human absorption, distribution, hepatic metabolism and toxicity, and some aspects of safety pharmacology, before a development candidate is selected.

4:45 PM - 5:30 PM

Screening Systems for Drug Transporters in the Liver, Kidney and Brain (Yuichi Sugiyama, University of Tokyo; Tokyo, JAPAN) Functions of influx and efflux transporters for drugs have to be evaluated separately. I will refer to MDR, MRP, OATP, OAT and OCT. Isolated cells, cultured cells and cDNA transfected cells can be used for evaluating the drug influx transporter activities. Membrane vesicles prepared from tissues and cDNA transfected cells can be used for evaluating the ATP-dependent efflux transporters such as MDR and MRP. Importance of the use of double transfectants (simultaneous expression of influx and efflux transporters) will be also discussed.

5:30 PM - 6:00 PM

Panel discussion: Virtual and in vitro approaches for the selection of drug candidates

END OF DAY

6:00 PM – 8:00 PM – Wine and Cheese Welcome Reception (not mandatory, casual dress)

Tuesday, December 3, 2002

C. Selection Based on Physical Chemical Properties

(Chair: Chris Lipinski)

8:00 AM – 9:00 AM CONTINENTAL BREAKFAST and REGISTRATION

8:00 AM – 5:00 PM - EXHIBITS

9:00 AM – 9:45 AM

Poor Aqueous Solubility: A Major Problem in Oral Drug Absorption (Chris Lipinski, Pfizer Global R&D, Groton, CT)

Poor aqueous solubility is the single largest physicochemical problem hindering oral drug absorption and lengthening drug discovery time in the current HTS / combinatorial chemistry era. Current experimental early discovery stage solubility screens differ markedly from traditional thermodynamic solubility assays. The solubility ranking of collections of chemical compounds can be estimated either from data mining, e.g. using the "rule of five" or from internal experimental solubility measurements or from calculations from among the many commercially available solubility programs. In terms of resource allocation there is no excuse for not understanding the likely solubility rankings of collections of compounds.

D. Omics: Expression Genomics

(Chair: Michael Carver)

9:45 AM –10:30 AM

Safety Assessment in the Early Stage of Drug Discovery: From Lead Selection/Optimization to Candidate Selection (Ikuo Horii, Pfizer Global Research & Development, Nagoya Laboratories, Aichi Pref., JAPAN) The toxicity studies required in the process of drug discovery can be categorized as toxicity studies for screening called “High-throughput toxicology” and exploratory toxicity studies for selecting candidates for EIH. In this paper, the following issues are pointed and discussed (1) Why safety evaluation needed in the early stage of drug development, (2) Paradigm shift of toxicology in drug discovery process, (3) What/how to evaluate in HTP-Tox studies.

10:30 AM – 10:45 AM – BREAK

10:45 AM – 11:30 AM

The Role of Drug Evaluation in Accelerating Discovery-Development Transitions (Marcus E. Brewster, Johnson & Johnson Pharmaceutical Research and Development, Beerse, BELGIUM) Drug discovery-Development bridging groups such as Drug Evaluation act as filters whose intent is to pass along only those drug candidates with a high probability of reaching the market. Given the limitations of time and compound availability, a number of in silico and high throughput methodologies have been developed to assess compound fitness especially in the pharmaceutical areas. An important component in this strategy is the use of BCS (Biopharmaceutical Classification Systems)-derived values obtained both though theoretical and experimental means.

Session II: Acceleration of Preclinical Studies

A. Selection of Relevant Animal Species for Preclinical Studies

(Chair: Rakesh Dixit)

11:30 AM – 12:15 PM

Selection of Relevant Animal Species to Support and Accelerate Non-clinical Toxicology Studies (Rakesh Dixit, Merck & Co., West Point, PA) Selection of appropriate laboratory animal species for non-clinical safety assessment studies is critical to predict the safety of investigational drugs for humans. General principles for the selection of appropriate animal species include, (a) similarity in metabolic profile and adequacy of systemic exposure, (b) ability of species to respond toxicologically and pharmacologically similar to humans, and (c) sensitivity to detect adverse effects, and (c) practical consideration with regard to toxicological and pathological procedures. The presentation will discuss approaches to selection of animal models for chemical and biological (e.g., biotechnology-derived) pharmaceutical agents will be discussed.

12:15 PM –1:30 PM – Net Working LUNCH (Sponsored By ISE, Inc.)

1:30 PM – 2:15 PM

Early Prediction of Human Pharmacokinetics for Drug Candidates With An Integrated In Vitro-In Vivo Approach (Jiunn Lin, Merck & Co.; West Point, PA) At the stage of drug discovery, it is essential that absorption and pharmacokinetic data be available for selecting lead candidates for further development. To facilitate an effective lead candidate selection, at Merck we have developed a strategy to implement and integrate in vitro and in vivo approaches to predict human bioavailability and pharmacokinetics. The purpose of the presentation is to discuss the applications and limitations of the integrated in vitro and in vivo approach.

2:15 PM – 2:30 PM - BREAK

2:30 PM – 4:00 PM

Panel Discussion: Approaches to predict human drug safety

END OF DAY

Wednesday, December 4, 2002

B. Acceleration of Carcinogenicity and Toxicity Bioassays Using Transgenic Animals

(Chair: Carl Alden)

8:00 AM – 9:00 AM – CONTINENTAL BREAKFAST and REGISTRATION

8:00 AM – 5:00 PM - EXHIBITS

9:00 AM – 9:45 AM
Strategic Utilization of Genetically Altered Models as Replacement for the lifetime Mouse Cancer Bioassay in the Drug Industry (Carl L. Alden, Page Bouchard, and Peter Smith, Millennium Pharmaceuticals, Cambridge, MA) The traditional rodent cancer testing paradigm typically results in tumor response with over 80% of the positives recognized as false positives. Furthermore, several of the most important human carcinogens in commerce do not test positive in the traditional rat and mouse lifetime bioassay including tobacco, cyclosporine, and arsenic. Since several drugs in the market place with sales in the billions of dollars cause multi-site multi-species tumors, the impact of tumor response in the absence of genotoxicity generally is recognized as minimal to nil. Despite this abysmal performance record of the traditional testing paradigm and despite the advent of improved models, many large pharmaceutical toxicology managers maintain status quo to stay within their comfort zone, recognizing that rodent tumor responses, if via nongenotoxic mechanisms, do not present serious barriers in development. (Alden, 2000) The TgrasH2 mouse model has better concordance with the human response to pharmaceuticals than does the lifetime mouse bioassay. The p53 “knock out” responds to human genotoxic carcinogens as effectively as the traditional lifetime mouse model. Utilization of either model presents over a 100% increase in efficiency, not to mention the reduced numbers of mice required for testing. The TG: AC model appears very promising using percutaneous exposure. The XPA/P53 KO double genetically altered model represents a strong concept but is in earlier stages of evaluation. Since toxicology testing in pharmaceutical development represents less than 2% of the total, cost has not had significant impact in driving change. The TgrasH2 and p53 models can be used efficiently and effectively to obviate the waste associated with a traditional lifetime mouse bioassay. The database on these two models is sufficient to enable reliable definition of the value in application. (Toxicologic Pathology, Vol. 29, Supplement)

9:45 AM – 10:30 AM

Development of transgenic Mouse to Predict Human Fetal Toxicity of Chemicals (Tetsuya Kamataki, Hokkaido University; Hokkaido, JAPAN) Unlike human fetuses, the fetuses of experimental animals do not possess enzymes responsible for the bioactivation of chemicals. Thus, it is impossible to predict the toxicity of chemicals, which exert their toxicity after undergoing the metabolic activation, using experimental animals in their fetal life. The purpose of this research was to establish Tg mouse expressing human CYP3A7, a major form of cytochrome P450 in human fetuses.

10:30 AM – 10:45 AM – BREAK

10:45 AM – 11:30 AM

Animal Models of Human Disease in Drug Safety Assessment (Urs A. Boelsterli, HepaTox Consulting and University of Basel, Basel, SWITZERLAND) Rare but severe adverse drug reactions, which often become apparent late in drug development or after launching, have in some cases lead to the discontinuation of further development or withdrawal of newly approved drugs from the market. These ADRs are a major problem because they have remained unpredictable from preclinical studies, and because their underlying mechanisms cannot be studied in normal healthy animals. One critical factor in the manifestation of a drug’s toxicity may be the underlying disease itself (indication for treatment), altering cell physiology and gene expression and eventually enhancing the toxic response to a chemical. This presentation focuses on the role of such disease factors that increase the risk for drug hepatotoxicity in animal models mimicking the human disease. Despite their obvious limitations, it is suggested that animal models of human disease be increasingly used, not only for new therapeutic approaches but also in preclinical toxicity studies as a powerful tool in candidate selection and mechanistic toxicology.

11:30 AM – 12:15 PM

Application of transgenic approaches to accelerate ADME and toxicology studies (Roland Wolf, University of Dundee, Scotland, UK) At the University of Dundee and at our recently launched biotechnology company, CXR Biosciences, we have a major interest in developing new models which will speed up the drug development process and also allow predictions to be made about how drugs will be handled in man. As part of this programme we are developing transgenic models for lead selection and development. An example of this is the recently developed model where we have deleted cytochrome P450 reductase conditionally from mouse liver. This model has generated a mouse with essentially no hepatic drug metabolism and provides an extremely powerful approach to understanding the role of the cytochrome P450 system in drug bioavailability and disposition as well in mechanisms of chemical toxicity. Additionally, we currently have a large collaboration with a number of pharmaceutical companies to develop high throughput in vivo toxicology screens. This project, also in collaboration with the Roslin Institute, Edinburgh, UK, aims to provide detailed information about potential chemical toxicity and toxic mechanism. The rationale for and application of these models will be described in this presentation.

12:15 PM – 1:30 PM – LUNCH

C. Acceleration of Drug Metabolism and Pharmacokinetics

(Chair: Yuichi Sugiyama)

1:30 PM– 2:15 PM

The Development and Implementation of Bioanalytical Strategies to Support ADME Studies in Early Drug Discovery. (Timothy Olah, Bristol-Myers Squibb; Anywhere, USA) With the increased speed at which potential drugs are now synthesized and evaluated for pharmacological activity, a need has arisen to also provide fundamental metabolism data at the early stages of drug discovery. The metabolic properties of a compound could be the deciding factor in whether or not it is selected for further development. Metabolic properties are related to the Absorption, Distribution, Metabolism and Excretion (ADME) of a compound following its administration. Other factors that influence a discovery team’s decision on which compounds to pursue include the assessment of metabolic stability, protein binding, P450 enzyme inhibition, and cell permeability in in vitro assays. Consequently, there is a substantial undertaking within the pharmaceutical industry to develop, validate and implement experimental procedures to evaluate selected metabolic properties of compounds in a higher throughput and more efficient manner.

2:15 PM – 3:00 PM

Taking Drugs from Laboratory Bench to the Clinic in Six Months Using Nanotechnology (Professor Colin Garner, CEO, CBAMS Ltd, York, United Kingdom) The standard paradigm of drug development needs to be radically re-engineered if drugs are to be brought to market faster. This can only be achieved through the rapid introduction of new enabling technologies such as accelerator mass spectrometry (AMS). AMS is an ultrasensitive nanotechnology, originally developed for carbon dating, which is being used by biomedical researchers to obtain early ADME and PK information about candidate drugs. In addition AMS is being used for biomarker analysis as surrogates of pharmacological effect. AMS has cut as much as 12 months from drug development times, saved animals and made first in man studies safer. The AMS technology will be described and some examples of its use presented.

3:00 PM – 3:15 PM – BREAK

3:15 PM – 5:00 PM

Panel discussion: Can transgenic animal carcinogenicity assays replace two-year bioassay for rodent carcinogenicity?

END OF DAY

Thursday, December 5, 2002

Session III: Acceleration of Clinical Studies

(Chair: Frank Sistare)

8:00 AM – 9:00 AM – CONTINENTAL BREAKFAST AND REGISTRATION

8:00 AM – 5:00 PM - EXHIBITS

A. Biomarkers for Human Toxicity in Clinical Studies

9:00 AM - 9:45 AM

Business Strategy for Biomarker Development and Applications in Drug Development. (Richard A Frank, Pharmacia Corporation; Peapack, NJ) Emerging technologies enable novel biomarkers and novel biomarkers enable innovative protocol design for clinical studies of drug effect. Whether innovative protocol design will in turn enable regulatory approvals of more efficient and accurate dossiers depends on a complex interaction among industry, government, and academia. New technologies are most useful as the basis for drug development if they can be used in the clinical setting, and particularly if they can be applied across multiple investigational sites. However, the greatest cost/benefit ratio, and least risk, may accrue to a biomarker when used in restricted circumstances simply to prove the concept that the drug penetrates to the site of action and the proposed mechanism of action is operative in the human. In this era of genomics, it is not infrequent that a second hypothesis remains to be tested, that this mechanism of action is relevant to some disease state and that a change in the marker reflects a clinically meaningful drug benefit. Biomarkers therefore fall into 3 distinct categories and should be recognized for their limitations and for their different validations needs. The development of biomarkers represents an investment that may be difficult to justify beyond the early business decision-making proof of concept.

9:45 AM – 10:30 AM

Application of Interspecies Biomarkers to Bridge Nonclinical Safety Evaluations to Clinical Drug Development (Frank Sistare, US FDA; Laurel, MD) Unacceptable toxicities are cited as one of the major reasons for the high failure rate of the drug development process. The essential challenges of nonclinical studies are to select the compound with greatest chance of clinical success, predict the expected human dose limiting toxicities for that candidate, predict whether the toxicity dose-response profile will allow the achievement of doses that will produce efficacy in humans, and establish the best starting dose for initiation of clinical trials. Not only would differences between humans and animal studies be expected, but also even wider differences in responses among humans might be expected. Critical decisions are made using the best available preclinical data to judge the impact of those expected differences on clinical drug development success. Data from animal studies are needed from drug developers to demonstrate for regulatory agencies a safe strategy for initiating human clinical trials. Since proof of drug efficacy in nonclinical studies is not a regulatory mandate, the focus of nonclinical studies is almost exclusively on defining toxicity parameters. In current regulatory toxicology practice, emphasis is heavy on measures of circulating drug molecule and metabolite concentrations as biomarkers of exposure that can be used as common “interspecies” reference points to guide clinical development plans. Often missing from these analyses however are easily accessible interspecies measures of toxicodynamic response. Understanding the relationship between drug exposure and alterations in such interspecies biomarkers has proven to be valuable for specific examples of regulatory decision-making, and when such biomarkers have not been identified impasses can develop. New technologies and new data are providing opportunities for incorporating valuable interspecies biomarkers for routinely monitoring early onset of serious toxicities, assuring that safe exposures are being achieved, evaluating relevance of animal toxicology findings, and for identifying patients at risk to help guide successful clinical development.

10:30 AM – 10:45 AM – BREAK

10:45 AM – 11:30 AM

Biochemical and Molecular Biomarkers of Toxicity: Applications and Limitations in Human Clinical Development (Rakesh Dixit, Merck & Co., Inc., West Point, PA) The lack of appropriate sensitive biomarkers of toxicity poses a major challenge to detection of clinical adverse effects in humans. The presentation will discuss the utility and limitations of non-invasive biomarkers of toxicity to detect and monitor adverse drug effects in humans. The applications of enzymes-based, genomics, proteomics, and metabonomics-based biomarkers of nephrotoxicity will be presented.

B. Optimization of Clinical Study Design Based on Preclinical Data

11:30 AM – 12:15 PM

Preclinical-to-clinical PK/PD Bridging in Development (Ryosei Kawai, Novartis Pharma K.K.; Tokyo, JAPAN) Various non-clinical studies are conducted in drug development. In vitro studies using cell/protein preparation are to identify and quantify factors influencing biologic and toxicological responses of candidate drugs as well as their pharmacokinetics. Animal in vivo studies are in principle to provide simulations of what may happen when the drug dosed to human/patients. A quantitative integration of all the non-clinical data, through physiologically-based, mechanistic PK/PD modeling, allows a logical, and often accurate, prediction of drug response in man, there by supports optimal designing of early clinical studies. The modeling exercise during clinical development phase relates data in healthy subjects and patients, also fostering breakdown of clinical finding into non-clinical studies.

12:15 PM – 12:30 PM - BREAK

12:30 PM - 1:15 PM

Clinical PK/PD study to accelerate drug development

(Yusuke Tanigawara, Ph.D.; Keio University Hospital; Tokyo, Japan) Recently, simultaneous development of new drugs among the ICH regions (U.S.A., EU and Japan) becomes more and more important to save time, cost and the number of patients. A useful concept, “bridging study” is proposed, which is defined as a supplemental study to provide pharmacokinetic, pharmacodynamic or clinical data on efficacy, safety, dosage and dose regimen in the new region that will allow extrapolation of the foreign clinical data package to the new region. The present talk introduces the fundamental idea of the bridging study and how to implement the clinical PK/PD approach into the internationally harmonized drug development.

1:15 PM – 2:00 PM

Integrating PK/PD Modeling and Simulation Approach for Clinical Trial Execution – A New Paradigm for Pharmaceutical R&D (Andrew T. Chow; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.; Raritan, NJ) Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is a reliable method to quantitatively characterize drug exposure-effect relationships. It has been utilized for decades in pharmaceutical research. Computer aided trial design (CATD) is an emerging technique that offers promises in predicting different trial design outcomes and its probability of success before conducting studies. It simulates virtual clinical trial results based on mathematical models that reflect PK/PD relationship, population distribution models of disease pathophysiology, and trial execution conditions. Integrating PK/PD modeling and simulation approach for clinical trial execution will help the pharmaceutical industry to transform drug research and development from a predominantly empirical process to a more predictive/confirmatory approach, thereby reducing inconclusive outcomes and unnecessary trials. Knowledge about a disease, drug behavior, and patient populations will be effectively captured and leveraged into future programs. This will result in reduction of overall time/cost in drug development and improve the quality of drug products. Examples of applying this approach in early drug evaluation and in full development projects will be presented.

2:00 PM - 3:00 PM

Panel Discussion: The reality of using early biomarkers for toxicity assessment in human clinical trials

END OF CONFERENCE

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Participating Exhibitors:

Xenotech, LLC; Lenexa, KS Huntingdon Life Sciences; East Millstone, NJ Quintiles; Morrisville, NC

Biotrin International; Dublin, IRELAND Human Biologics, Scottsdale, AZ Amphioxus Cell Technologies; Houston, TX