이전 학기에 Tozer를 마치고 새로운 책으로 Book reading을 시작하게 되었습니다. 약물 개발의 성패를 좌우할 수 있는 초기 단계의 전반적인 이해와 활용에 대해 굉장히 유용한 책입니다. 아래와 같이 요약하고자 합니다.

Early Drug Development - Strategies and Routes to First-in-Human Trials by Mitchell N. Cayen

Chapter 1. The Drug Discovery and Development Scene

Introduction

• 신약 개발의 어려운 점 서술.
• NCE (New Chemical Entity)
• “Bigger is Better” philosophy
• Rule of Five (Lipinski) - 5개 이하 hydrogen bon, 10 bond acceptors, < 500kDa
• Hit-to-Lead Identification
• SAR: Structure-activity compounds
• Small molecule to various new entities
• Table 1.1 - Some Optimal Characteristics Evaluated During the Discovery Phase for Orally Administered Drugs
• Toxicogenomics - Possible alternative to animal tox testing
• “Can it replace the animal models?”
• Permeability and transporter assays -> drug uptake into or efflux from the target organ
• PK뿐 아니라 PD 측정하면 이상적일 것이다(Extremely useful).
• EMEA, FDA, MHLW (Japan)

CRO (Contract Research Organizations)

• CRO를 잘 골라야 한다. 문화를 잘 관찰

Chapter 2. ADME strategies in lead optimization

• speaker: Park
• date: 2016-10-25
• Lead optimization - several screens to select an NCE with the best overall efficacy, ADME/PK
• in silico adme screening
• data-based modeling
• log P(partition coefficient), log D (log P using buffer at pH7.4) - charge 띈게 많은 것을 고려함.
• basic requirements for successful in silico modeling
• 구조를 입력하면 대사에 대한 정보가 나옴.
• Metabolomics - 대사체를 분석하는 것이 많은 정보를 줄 수 있다.

Chapter 5. Chemistry, Manufacturing, and Controls

• in vitro pharmacology
• Pre-NCE activities and CMC development
• Crystal forms - Table 5.5
• preformulation
• 특징화, 제제화
• GMP, LBP
• 특징화되어야 한다.
• Toxicology Formulations
  • later Stages of tretm

Chapter 7. Toxicology Program to Support Initiation of a CLinical Phase I Program For a New Medicine

• Nonclinical safety margin
• 비임상 개발 review시에도 physician이 참가해야 한다.
• Inactive ingredients -> FDA approval.
• Timely Conduct
• Ames - IND 필수 항목. Regulatory submission of IND.
• if + in Ames -> similar pharmacologic activity and negative in the Ames assay.
• 미국 IND, 영국 CTA, 12-18 months
• 28 days. Maximum duration of dosing that can occur in the human studies
• No observable effect level
• HNSTD - Highest nonsevere toxic dose - NOAEL보다는 좀더 높다. Severe adverse events가 나타나지 않는 최대의 용량을 말하는 것.
• IND - regulatory requirement, guidelines, safety, controlled condition->synthesized.
• pre-FIH toxicity studies - providing a basis for selection of the initial dose
• 1/10 NOAEL 1/6 non rodent
• Toxicology만 받았는데.. 앞으로는 efficacy 측면에서 효과를 보여야 할지도 모른다.