LOP

Cambridge Healthtech Institute 第1回

Lead Optimization for Drug Metabolism and Safety

( 薬物安全性の向上を目的としたリード化合物の最適化 )

薬剤設計に安全性の考え方を組み込むための手段と戦略

2018年4月6日 | | Hilton Bayfront | カリフォルニア州サンディエゴ

 

化合物の構造が薬らしい特性に影響を及ぼす可能性についての知識が増えることで、医薬品開発のためこれらの特性を最適化する作業も短縮することができます。創薬におけるリード化合物は、効能と安全性の両面で最適化が必要ですが、化合物にまつわる有害事象のなかには、かなり後の開発段階まで表面化しないものもあります。薬物安全性の向上を目的としたリード化合物の最適化をテーマに終日開催されるこのシンポジウムでは、薬物代謝と薬物動態 (DMPK) 、安全性薬理学、毒性研究などの分野の専門家が一堂に会し、とりわけ安全性に関する懸念への対応を目的とした最初期段階でのリード化合物の最適化に関して考慮すべき要因について議論します。シンポジウムでは、入門レベルの講演から薬理学と毒物学の最先端の研究を紹介するものまで多彩なセッションが予定されており、ケーススタディや研究成果を利用した先進的なコンセプトにもスポットライトが当てられます。創薬化学、医薬品化学、薬剤設計、薬物の吸収・分布・代謝・排泄 (ADME) と薬物動態学/薬力学 (PK/PD) 、計算化学などさまざまな領域の研究者がリード化合物の同定と最適化をめぐって活発な議論を展開するこのシンポジウムをどうぞお見逃しなく。


Final Agenda

4月6日 (金)

7:25 am Registration and Morning Coffee

薬物代謝と薬物間相互作用の解明

7:55 Welcome and Opening Remarks

Tanuja Koppal, PhD, Conference Director, Cambridge Healthtech Institute

John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.


8:00 FEATURED PRESENTATION: Addressing Biotransformation Issues in Early Discovery

Deepak Dalvie, PhD, Senior Director, DMPK, Celgene

Drug metabolism plays an important role in the discovery and development of a drug candidate. Addressing metabolism issues early on can result in candidates with less metabolism as well as bioactivation liabilities.  Strategies and examples of role of metabolism in early discovery will be discussed in this talk. 

8:30 Principles of Metabolite Identification by Mass Spectrometry for Drug Discovery and Development

John C. L. Erve, PhD, DABT, Consultant, Jerve Scientific Consulting, Inc.

Metabolite identification (Met ID) studies are an important component for both drug discovery and drug development efforts. Mass spectrometry, particularly high mass accuracy techniques, is the primary tool for Met ID studies. Chemists often rely on internal or external scientists to perform metabolite identification and characterization but will benefit by understanding how it is done. This talk will cover strategies used to identify drug metabolites allowing chemists to better understand the strengths and limitations of these studies.

9:00 Coffee Break

薬物輸送と薬物クリアランスの影響

9:30 Detection and Assessment of Reactive Drug Metabolites in Drug-Mediated Hepatotoxicity

Mark Grillo, PhD, Staff Scientist, Drug Metabolism & Pharmacokinetics, MyoKardia, Inc.

A number of toxic drugs undergo bioactivation to chemically-reactive metabolites that bind covalently to endogenous macromolecules, proteins, DNA leading to organ toxicity and carcinogenesis. Current experimental techniques used to detect and assess the potential liabilities of reactive metabolites and how information from mechanistic in vitro studies can be employed to redesign candidate drugs leading to blocked or minimized bioactivation and decreased toxification will be discussed.

10:00 Application of Drug Transporters in Drug Discovery

Caroline Lee, PhD, Executive Director, Ardea Biosciences Inc., a member of the AstraZeneca Group

Transporters play a key role in the disposition of drugs. Transporters contribute to drug efficacy, drug interactions and may limit desired drug exposure. The rationale and identification of the transporters to implement in drug discovery will be discussed as well as the difficulties that may be encountered in translating in vitro data to clinical outcome.

10:30 Addressing the Challenges of Low Clearance and Intracellular Free Drug Concentration

Li Di, PhD, Research Fellow, Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc.

Low clearance compounds continue to increase in drug discovery and lack of low clearance tools can lead to over-prediction of clearance, dose and under-prediction of half-life. Intracellular free drug concentration is most relevant for development of PK/PD relationships and prediction of drug-drug interactions. This presentation will discuss approaches to address these challenges and their applications in drug discovery.

11:00 Sponsored Presentation (Opportunity Available)

11:15 Luncheon Presentation (Opportunity Available) or Enjoy Lunch on Your Own

12:00 pm Session Break

ケーススタディ:DMPK特性最適化のための戦略

1:00 Chairperson's Remarks

Mark Grillo, PhD, Staff Scientist, Drug Metabolism & Pharmacokinetics, MyoKardia, Inc.

1:05 Use of Integrated DMPK Approaches to Facilitate Design of Brain Penetrant Kinase Inhibitors

Xingrong Liu, PhD, Principal Scientist, Drug Metabolism and Pharmacokinetics, Genentech, Inc.

1:35 A Proposed ADME Optimization Workflow for Covalent Inhibitors

Mehran Moghaddam, PhD, MBA, Founder and CEO, OROX Biosciences

With the renewed interest in covalent inhibitors comes the responsibility to advance only compounds with drug-like properties in discovery programs. The traditional small molecule reversible drug discovery workflow includes target identification and validation, lead identification, lead optimization and profiling and optimizing for ADME properties are paramount in obtaining acceptable efficacy and safety. This presentation will contrast the ADME workflow for discovery of covalent verses reversible inhibitors.

2:05 Predicting Human PK and Exposure in Discovery to Inform Lead Optimization and Candidate Selection

Natalie Hosea, PhD, DMPK San Diego Site Head, Takeda

Prediction of human pharmacokinetics and drug-related exposure underpins early decision-making in drug discovery. More specifically, early human predictions enable identification of key liabilities for focused optimization strategies as well as enabling assessment of early safety information when coupled with pharmacology information. In this section, case studies on the application of predictions to optimization strategies and compound advancement will be discussed.

2:35 Co-Presentation: Strategies and Application of CYP Inhibition and Phenotyping Assays to Optimize SYK Inhibitor Drug-Drug Interaction Risk Profiles

David M. Stresser, PhD, Principal Research Scientist, AbbVie, Inc.

Michael Hoemann, PhD, Senior Scientist, Department of Chemistry, AbbVie, Inc.

Cytochrome P450 interaction liabilities receive higher scrutiny in therapeutic areas requiring low tolerance for drug-drug interactions. In these competitive market areas, rapid access to robust CYP metabolism and inhibition data is crucial to a program's success. We will review early 'perpetrator' and 'victim' assays and how they were used at AbbVie to successfully address a significant FmCYP3A4 and time-dependent inhibition liability in a Spleen Tyrosine Kinase (SYK) program.

3:05 Refreshment Break

薬物動態毒性 (ADMET) の予測と初期投与のための新たなアッセイ

3:35 Kriging - A New Approach for Building ADMET Prediction Models

Istvan Enyedy, PhD, Principal Scientist, Medicinal Chemistry, Biogen

Kriging is using the correlation of the distance between molecules with the difference between their activity/ADMET properties for in silico predictions. We have considered this algorithm since it allows us to easily build, evaluate, and maintain models and has a report format that allows users to judge the accuracy of the predictions. The performance of eighteen models and how training sets impact it will be presented.

4:05 Sensitive in vitro Screening for Structure/Tissue Toxicity Assessment with Rapid-Turnaround Time

Ian Sweet, PhD, Associate Professor, Department of Medicine, University of Washington

I will present sensitive technology we have developed that continuously measures time courses of pharmacologically relevant drug effects on solid tissue samples. The accuracy and throughput is well suited to quantify and rank effects and toxicity of drug metabolites, chemical libraries and lead candidates. Data generated will be useful for the analysis of drug effects on human vs. animal tissue, target organs and drug-drug interactions.

4:35 In vitro Tools for Successful Prediction of Human Hepatic Clearance

Jasleen Sodhi, Graduate Student, Laboratory of Dr. Leslie Benet, Pharmaceutical Sciences and Pharmacogenomics Program, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco

Accurate prediction of human pharmacokinetic properties is critically important in drug discovery. Of particular importance is the prediction of hepatic clearance, which largely determines drug exposure and contributes to projections of dose, drug half-life and bioavailability. This talk will cover common in vitro techniques used to predict hepatic clearance of new chemical entities and the fundamentals of in vitro to in vivo extrapolation (IVIVE) of drug clearance.

5:05 End of Conference

* 不測の事態により、事前の予告なしにプログラムが変更される場合があります。