Dermal Drug Selection and Development: An Industrial Perspective

ISBN-13: 9783319866390 / Angielski / Miękka / 2018 / 148 str.

Lionel Trottet; Howard Maibach MD

Recenzje

"This book provides some valuable insights into the challenges related to the design and development of dermatopharmaceuticals. As such, this book is expected to be well received by the scientific community involved in this kind of research. ... this book should serve as a reference for anyone interested in developing dermatopharmaceuticals. ... Written by an expert in drug delivery, this book provides an overview of challenges the industry faces in selecting and developing a dermal product." (Rahmat M. Talukder, Doody's Book Reviews, September, 2017)

Spis treści

CHAPTER 1. INTRODUCTION 7

1.1. Developing a new medicine

1.2. Key risks at the candidate selection stage

1.3. Attrition in the pharmaceutical industry

1.4. Evolution of the Pharma R&D over the last 2 decades

1.5. Pharma R&D productivity in decline

1.6. Cost of Pharma R&D and cost up to Candidate selection

1.7. Increased risks to develop a topical drug

1.8. Increased opportunities to develop a topical drug

CHAPTER 2. CHOOSING THE TOPICAL DRUG CANDIDATE : AN HISTORICAL OVERVIEW 19

2.1. The pragmatic topical drug development approach: An existing oral/systemic drug is further developed as a topical

2.2. Moving towards improved topical drug candidate selection processes: Use of in vivo models

2.3. Historical topical drug candidate selection summary

CHAPTER 3. KEY FACTORS AFFECTING THE EFFICACY OF A TOPICAL DRUG CANDIDATE: LEARNINGS FROM PAST

TOPICAL DRUG DEVELOPMENT 31

3.1. Skin barrier condition vs. “Easiness” of topical drug development

3.2. Drug potency and clinical efficacy

CHAPTER 4. TOPICAL VS ORAL/SYSTEMIC DRUG DISCOVERY 40

4.1. Drug Discovery Evolution

4.2. Oral/Systemic Drug Discovery

4.3. Topical Drug Discovery

4.4. The Two Key Differences in discharging risk in between the Oral/Systemic and Topical Drug Discovery Processes

4.5. Consequences for the Preclinical Stage: “Maximising the Percutaneous Flux”

4.6. What can be learned from the Oral Drug Development Process?

CHAPTER 5. ASSESSING DRUG CONCENTRATION IN SKIN: DIRECT AND INDIRECT METHODS 52

5.1. Direct Methods

5.2. Indirect Methods

5.3. Potential Use of the various skin PharmacoKinetic Sampling Methods, Comparisons of the Methods  and Consequences

5.4. Using the Percutaneous Flux or the Plasma concentrati

on as surrogate measurement of skin concentration

CHAPTER 6. ASSESSING TOPICAL EFFICACY 72

6.1. Assessing efficacy and dose prediction for a systemic target

6.2. In vivo PD Models:

6.3. Conclusion

CHAPTER 7. ASSESSING THE THERAPEUTIC INDEX 86

7.1. Introduction

7.2. A “crude” Approach: Comparing the mass of target tissue with total body mass

7.3. Calculated Approach

7.4. Comparative Approach

CHAPTER 8. TOPICAL VEHICLE SELECTION: MYTHS AND REALITY 93

8.1. Introduction : 

8.2. Skin Penetration Enhancement

8.3. Retention in Skin

8.4. For each compound, a specific formulation: A must ?

8.5. Vehicle Aesthetics

8.6. Drug formulated as a dispersion or as a solution?

8.7. Conclusion

CHAPTER 9. TOPICAL DRUG DEVELOPMENT STRATEGIES 107

9.1. Option#1: Clinical molecule repurposing - Developed drug f

or a non systemic indication on a new target class

9.2. Option#2: Full lead optimization - New drug from a new mechanism of action for a topical application

9.3. Option#3: “Me better” - Improved drug for a known topical target class

9.4. Option#4: Chemical Series Repurposing - Advanced lead optimized chemicals series screened against for a topical indication

CHAPTER 10. TOPICAL DRUG CANDIDATE SELECTION CRITERIA AND CASCADE 111

10.1. General principles: Discharging risk

10.2. Medicinal chemistry and chemical space

10.3. Potency

10.4. Percutaneous Flux

10.5. Pharmacological Kinetics Response

10.6. Preclinical Proof of Concept

10.7. Solution Stability – Water Stability

10.8. UV Absorption

10.9. Local Irritation

10.10. Systemic Effect (Clearance & Protein Binding)

10.11. Other criterias not important for a topical candidate

10.12. Comparison of the criterias used to select an oral/systemic candidate and a topical one

10.13. Example of candidate selection cascade when repurposing a whole chemical series

CHAPTER 11. SELECTING A DERMAL DRUG CANDIDATE: SOME USEFUL QUOTATIONS AND RULES 127

CHAPTER 12. CONCLUSIONS AND PERSPECTIVES 131

O autorze

Lionel Trottet, PhD is a DMPK Unit Manager, Drug Discovery chez Oncodesign in France. He has 20 years of expertise in Dermatology (dermal drug discovery, pharmacokinetics, PK/PD and formulation), 18 years of experience in general pharmacokinetics, drug metabolism and PK/PD, 13 years of experience as a DMPK representative in Drug Discovery projects, and 8 years of experience as a DMPK manager.

Howard Maibach, MD is an expert in contact and occupational dermatitis and sees patients at the Environmental Dermatosis Clinic, which is part of the Dermatology Clinic at University of California, San Francisco (UCSF). His specialty is dermatotoxicology, or skin exposure toxicity; allergies and skin disorders; and dermatopharmacology or the study of medications for skin disorders. Dr. Maibach has been on the editorial board of more than 30 scientific journals and is a member of 19 professional societies including the American Academy of Dermatology, San Francisco Dermatolo

gical Society and the Internal Commission on Occupation Health. He is a professor in the Department of Dermatology at UCSF.

Blurb

The authors show how the pharmaceutical industry faces the development of dermal drugs and provide the only book of its kind that describes how the industry develops and selects dermal drugs, complete with the challenges and opportunities of the field. Delivery of drugs through the skin has been an attractive and challenging area for research, and advances in modern technologies have resulted in a larger number of drugs being delivered transdermally, including conventional hydrophobic small molecule drugs, hydrophilic drugs and macromolecules. Offering the perspective from the industrial side of selection and development of drugs, the primary audience is geared towards the pharmaceutical industry but can also offer valuable information to clinicians, compounding pharmacists, and similarly pharmacy students. Dermal Drug Selection and Development covers the

scientific gaps that exist in terms of dermal pharmacokinetics and the resulting uncertainty by clinicians when choosing a drug candidate.