ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins PDF Free Download : Applications in Drug Discovery and Development
The use of biologically derived sources for the treatment or amelioration of diseases and conditions is as old as the existence of the human race. But most extracts and preparations from plants and animals were un‐ or ill‐defined mixtures, without a clear understanding of the active ingredients, if any. The past 50 years has seen a transformational change with the development and availability of so many new specific and potent drugs to address a myriad of previously unmet medical needs. Although the first few decades of this period, from the 1960s to 1980s, was the age of small molecular entities, the last two decades can be said to be the age of the emergence of the large drug molecule, comprising approximately 35% of all new drugs approved during this latter period. This successful development of a plethora of large (often recombinant) molecules is one of the fruits of the preceding explosion in molecular biology and biotechnology; hence the term therapeutic biologics. They span a dizzying array of compounds of varying molecule size and complexity, from relatively simple molecules, such as insulin, to antibodies, to vaccines, and beyond. What they share in common, and in contrast to most small molecular weight drugs, are the building blocks, namely amino acids.
Also because of lability of many protein drugs in the gastrointestinal tract, they often need to be administered parenterally to be therapeutically effective, in contrast to small molecular weight drugs for which the oral route is the most common. This book is about the absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetics/pharmacodynamics (PK/PD) of protein drugs, in particular, but not exclusively, monoclonal antibodies, primarily because so many of the currently approved protein drugs, and likely future ones, are of this class. Unlike many small molecules, which access all sites within the body, including intracellular targets, currently most protein drugs tend to be restricted to extracellular targets, because of their relatively large size and polarity. Even so, there are issues regarding the movement of protein drugs from the vascular to target sites within the tissue interstitial space. The need for this book exists because it has become clear that although there are some similarities, many of the processes that operate or apply to small molecular weight drugs and guide their development do not apply, or are less explicable, to protein drugs, about which our understanding is at an early stage. Still, there are lessons to be learned from our experience with small molecular entities. Before the 1950s, the development of small molecular weight drugs was based almost exclusively on final outcomes, efficacy, and safety, with virtually no concern as to what happened to a drug within the body upon its administration. The thalidomide catastrophe in the 1960s and the lifethreatening terfenadine–ketoconazole interaction in the early 1990s were among landmark events that focused (regulatory) attention on the need to better understand the ADME processes controlling the fate of such drugs within the body and effects on the body. Also, linking PK/PD was seen as the way forward to quantitatively map the dose–response–time surface within the patient population to better inform the design and development of optimal dosage regimens.
ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins PDF Free Download, ADME and Translational Pharmacokinetics / Pharmacodynamics of Therapeutic Proteins PDF Ebook Free