Brady Kevin, Webster Rob
Bicycle Therapeutics Ltd., Cambridge, United Kingdom.
Adv Pharmacol. 2012;63:257-77. doi: 10.1016/B978-0-12-398339-8.00007-0.
Drug development is a complex process, requiring scientific and regulatory input at almost all stages from multiple groups of expertise. Small molecule development issues are covered in other parts of this volume. This chapter is devoted to discussing the large molecules, or biologics, and the particular nuances involved in developing these molecules as medicines. Our definition of biologic, for the purposes of this chapter, differs from that described by the regulatory bodies. Where regulators state that a biologic is a molecule produced by a living organism, be it a mammalian, insect, yeast or bacteria cell, or whole animal, we prefer to include molecules such as oligonucleotides and peptides here, which are usually chemically synthesized. So our definition is that of a molecule whose composition mostly entails naturally occurring amino acids, sugars or nucleotide bases. There are modifications made chemically to oligonucleotides and peptides to improve their drug-like properties, but for this volume, we class them as biologics. The aim of this chapter is to describe some of the differences, complexities and paradoxically, simplifications in the pharmacokinetics and ADME sciences during drug development of biologics when compared to the more familiar small molecule drug development process. The impact of the particular pharmacokinetics and ADME sciences of biologics on toxicological and pharmacological end points will be discussed.
药物研发是一个复杂的过程，几乎在所有阶段都需要来自多个专业领域的科学和监管投入。小分子药物研发问题在本卷的其他部分有涉及。本章致力于讨论大分子药物，即生物制品，以及将这些分子开发成药物过程中所涉及的特殊细微差别。就本章而言，我们对生物制品的定义与监管机构所描述的不同。监管机构指出生物制品是由活生物体产生的分子，无论是哺乳动物、昆虫、酵母或细菌细胞，还是整个动物，而我们更倾向于将寡核苷酸和肽等分子也包括在这里，它们通常是化学合成的。所以我们的定义是其组成主要包含天然存在的氨基酸、糖类或核苷酸碱基的分子。对寡核苷酸和肽进行了化学修饰以改善其类药物性质，但在本卷中，我们将它们归类为生物制品。本章的目的是描述与更为熟悉的小分子药物研发过程相比，生物制品药物研发过程中药代动力学和药物代谢动力学及排泄科学方面的一些差异、复杂性，以及矛盾之处——即简化之处。还将讨论生物制品特殊的药代动力学和药物代谢动力学及排泄科学对毒理学和药理学终点的影响。
