Early Drug Development, 2 Volume Set

This one-stop reference systematically covers key aspects in early drug development that are directly relevant to the discovery phase and are required for first-in-human studies,
Its broad scope brings together critical knowledge from many disciplines, ranging from process technology to pharmacology to intellectual property issues,
After introducing the overall early development workflow, the critical steps of early drug development are described in a sequential and enabling order: the availability of the drug substance and that of the drug product, the prediction of pharmacokinetics and -dynamics, as well as that of drug safety, The final section focuses on intellectual property aspects during early clinical development, The emphasis throughout is on recent case studies to exemplify salient points, resulting in an abundance of practice-oriented information that is usually not available from other sources,
Aimed at medicinal chemists in industry as well as academia, this invaluable reference enables readers to understand and navigate the challenges in developing clinical candidate molecules that can be successfully used in phase one clinical trials,

Fabrizio Giordanetto graduated in Medicinal Chemistry (Genoa, Italy) followed by his Ph,D, (London, UK) while working for the chemistry unit of Pharmacia - Pfizer (Italy), After positions at AstraZeneca (Sweden) as Principal Scientist and Project Leader and at Taros (Germany) as Head of Medicinal Chemistry, he has recently joined DE Shaw Research LLC (New York, USA) where he leads medicinal chemistry activities and drug discovery projects, During his career, he worked on several drug discovery programs resulting in multiple clinical candidates spanning oncology, CNS, inflammation, metabolic and cardiovascular indications and 100 international patents, peer-reviewed publications and book chapters,

Auteur

Fabrizio Giordanetto graduated in Medicinal Chemistry (Genoa, Italy) followed by his Ph.D. (London, UK) while working for the chemistry unit of Pharmacia Pfizer (Italy). After positions at AstraZeneca (Sweden) as Principal Scientist and Project Leader and at Taros (Germany) as Head of Medicinal Chemistry, he has recently joined DE Shaw Research LLC (New York, USA) where he leads medicinal chemistry activities and drug discovery projects. During his career, he worked on several drug discovery programs resulting in multiple clinical candidates spanning oncology, CNS, inflammation, metabolic and cardiovascular indications and >100 international patents, peerreviewed publications and book chapters.

Échantillon de lecture
1
Early Drug Development: Progressing a Candidate Compound to the Clinics: Introductory Remarks

Fabrizio Giordanetto

D. E. Shaw Research, Department of Medicinal Chemistry, 120 W. 45th Street, New York, NY, 10036, USA

Drug discovery and development is a fascinating, challenging, and multidisciplinary process where ideas for therapeutic intervention are devised, evaluated, and translated into medicines that will ultimately benefit society as a whole. As the name implies, it consists of mainly two elements: an initial discovery phase, followed by a development phase. These two phases differ significantly from each other with respect to scope, challenges, and approaches. As an example, while discovery experiments are typically executed in a laboratory setting using isolated and approximate systems (e.g. recombinant protein, cells, animals), development experiments consist of clinical trials in hospitals with human subjects and their full pathophysiological complexity. Differences notwithstanding, discovery and development must be integrated into a coherent whole for the process to be successful. Accordingly, much thought has been devoted to ensure scientific, logistical, and organizational aspects of such integration are taken into consideration and optimized [1-4].

Thankfully, the early view (and practice) of a discovery unit tasked with the delivery of a compound, typically termed a "preclinical candidate," which is then "thrown over the fence" to the development organization responsible for its clinical progression as a candidate drug, is a memory from a (not so) distant past. Alignment of research objectives and outcomes relevant to the discovery phase with clinical imperatives relevant to the development phase and commercial viability is not always straightforward, especially in new sectors of the pharmaceutical research environment where innovative therapeutic hypotheses are speculative and not clinically validated. Nevertheless, such an alignment is absolutely required for success, and a joint understanding and ownership of the practical implications of such alignment needs to be fostered within the project teams and their organizations.

Conceptual tools to support the initial definition of discovery and development alignment at a project level, and the strengthening of this alignment as the drug hunting program evolves, have been developed and provide a useful framework [5, 6]. Unsurprisingly, early drug development is where this alignment between discovery and clinical requirements is crystallized, normally by the selection of one or more compounds that fulfill a predefined profile, that will be progressed to clinical studies.

The definition of this so-called target product profile ( [7]) affects all research activities during lead optimization, including focused compound design in order to reach the set TPP standards, and planning of a screening cascade in order to maximize the number of testing cycles on key TPP parameters. Some salient TPP properties such as toxicological risks, predicted human dosing, and pharmaceutical properties can only be effectively, and practically, assessed for the first time in a project timeline during early drug development. TPP definition and compliance have therefore far-reaching effects across the drug discovery-drug development value chain: they dictate which compounds are made in the first place, which compounds will be selected for clinical development, and ultimately which compounds will be successful at the end of the development cycle.

This book is structured around the TPP to highlight its importance as an early drug development compass. Here, we set the compound(s) of interest - one of which is destined to become the new drug substance - front and center because the experimental quantities relevant to the TPP, reg

Contenu

Contents to Volume 1

Preface xv

A Personal Foreword xix

1 Early Drug Development: Progressing a Candidate Compound to the Clinics 1
Fabrizio Giordanetto

References 7

Part I Drug Substance 9

2 Early Phase API Process Development Overview 11
J. Christopher McWilliams and Mark Guinn

3 The Discovery/Development Transition 31
Christopher M. Cimarusti and David R. Kronenthal

4 Active Pharmaceutical Ingredient Cost of Goods: Discovery to Early Development 49
Neal G. Anderson and Todd D. Nelson

5 New Technologies in Process Development 73
Peter W. Sutton, Joseph P. Adams, Charles Wade, and Katherine Wheelhouse

6 Vortioxetine and Early Drug Development Considerations at the Interface of R&D 125
Morten Jørgensen, Kim Christensen, Martin Juhl, and Benny Bang-Andersen

7 Development of a Practical Synthesis of 4-Azido-2-Methyl-2-Desoxycytosine and Its Prodrugs as HCV Chemotherapeutic Agents 145
Sébastien Lemaire, Tom Govaerts, and Vittorio Farina

Part II Drug Product 169

8 Solubility, Permeability, and Their Interplay 171
Avital Beig, Milica Markovic, and Arik Dahan

9 Solid-State Properties 203
Si-Wei Zhang, Robert F. Dunn, and Alfred Y. Lee

10 Salt and Cocrystal Screening 229
Ann Newman, Cen Chen, and Carlos Sanrame

11 Particle Size Reduction: From Microsizing to Nanosizing 271
Dedong Wu and Beth A. Sarsfield

12 Early Drug …