Dermal Drug Selection and Development: An Industrial Perspective

by Lionel Trottet, Howard Maibach, MD

Overview

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.

Product Details

ISBN-13:	9783319595030
Publisher:	Springer International Publishing
Publication date:	08/08/2017
Edition description:	1st ed. 2017
Pages:	148
Product dimensions:	6.10(w) x 9.25(h) x (d)

About the Author

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

Table of Contents

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 concentration 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 for 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

Editorial Reviews

Reviewer: Rahmat M. Talukder, PhD, RPh (The University of Texas at Tyler)
Description: This book offers scientific perspectives on how the industry addresses various challenges in selecting a drug candidate and developing it as a dermal drug product. Written by experts working in this field, this book provides practical information on the topics with necessary references.
Purpose: The objective is to provide an overview of fundamental aspects of development of dermatopharmaceuticals. For systemic actions, a drug molecule must be in appropriate concentrations at the site of its action. Because skin is a tough barrier to passage of a drug into systemic circulation and thereby to its site of action, selecting a drug candidate and developing it in a dermal dosage form is a challenge. 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.
Audience: While the authors do not specify an audience, this book should serve as a reference for anyone interested in developing dermatopharmaceuticals.
Features: This book presents scientific perspectives on the design and development of dermal products. An overview of historical perspectives of topical drugs is succinctly presented. One feature, "Selecting Dermal Drug Candidates: Some Useful Quotations and Rules," is interesting and may be helpful for a team working towards developing dermal products. In chapter 3, the authors very briefly describe easy and difficult drug classes for developing dermal products. In chapter 4, two separate flow charts of oral and topical drug discovery objectives and risk discharge are handy. Though brief, the chapter on dermal efficacy assessment is helpful. The chapter presenting various criteria to select a drug candidate for dermal product development seems to be useful. The book ends with conclusions and perspectives on future developments in dermal drug delivery. A chapter on regulatory issues and development of generic dermal products would be appropriate. While "topical" refers to local and "dermal" includes local as well as systemic drug delivery, it appears that the authors use "topical" and "dermal" interchangeably. The authors' description indicates that the therapeutic window of a drug candidate is related to its dosage forms. In biopharmaceutics, therapeutic window refers to the plasma drug concentration range that provides safe and effective therapy, i.e., therapeutic window is directly related to pharmacological and toxicological properties of a drug substance rather than to its delivery method. The book needs copyediting.
Assessment: Similar to other drug product development, selection of a drug candidate for its development as a dermal product is a complex process and requires an understanding of basic scientific principles. Written by an expert in drug delivery, this book provides an overview of challenges the industry faces in selecting and developing a dermal product. There is plenty of room for improvement in this book. Nevertheless, industry professionals involved in the development of dermatopharmaceuticals can expect to find it somewhat useful.

Doody's Review Service

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)

From the Publisher