CHAPTER 1. INTRODUCTION 71.1. 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 192.1. 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 models2.3. Historical topical drug candidate selection summary CHAPTER 3. KEY FACTORS AFFECTING THE EFFICACY OF A TOPICAL DRUG CANDIDATE: LEARNINGS FROM PAST TOPICAL DRUG DEVELOPMENT 313.1. Skin barrier condition vs. "Easiness" of topical drug development 3.2. Drug potency and clinical efficacy CHAPTER 4. TOPICAL VS ORAL/SYSTEMIC DRUG DISCOVERY 404.1. 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 525.1. 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 726.1. Assessing efficacy and dose prediction for a systemic target 6.2. In vivo PD Models: 6.3. Conclusion CHAPTER 7. ASSESSING THE THERAPEUTIC INDEX 867.1. 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 938.1. 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 1079.1. 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 11110.1. 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.
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.