Biopharmaceuticals factors

Absorption from the Gl tract is governed by many factors. Broadly, it can be categorized into three classes physicochemical properties, biopharmaceutical factors, and physiological and pathophysiological factors (Mojaverian et al., 1985,1988 Nomeiretal., 1996). Since this chapter focuses on the pharmacokinetic perspectives, the main factors that could affect drug absorption are merely listed below, and will be discussed in detail in other chapters. 

Hurst, S., Loi, C. M., Brodfuehrer, J., and El-Kattan, A. (2007). Impact of physiological, physicochemical and biopharmaceutical factors in absorption and metabolism mechanisms on the drug oral bioavailability of rats and humans. Expert Opin. Drug Metab. Toxicol. 3 469-489. 

Almost all drug-macro molecule interactions occurring in the body show chiral discrimination. This is true whether they are drug-enzyme or drug-receptor in nature. The situation is complicated further because some drugs show stereoselective absorption, distribution and excretion between enantiomers and it is difficult to determine which effects are due solely to metabolism and which are due to other biopharmaceutical factors. 

Pharmacokinetic and Biopharmaceutical Factors Important for Pulmonary Targeting... 

Chapter 4 describes the importance of drug delivery and biopharmaceutical factors in the candidate drug selection phase. Consideration is given to the intended route of administration and what predictions can be made and useful information gained from biopharmaceutical assessment of the candidate drug. 

Biopharmaceutical factors in parenteral administration of vitamin E, Pharm. Sci., 64 655. 

The principal considerations involved in design of a process-scale chromatographic purification include scalability, reproducibility, safety, and validatability. Cost factors, however, must by necessity enter into all industrial decisions. Due to the high value-added nature of most biopharmaceuticals, this cost factor is driven by throughput, rather than by capital investment cost. 

Many of the initial biopharmaceuticals approved were simple replacement proteins (e.g. blood factors and human insulin). The ability to alter the amino acid sequence of a protein logically coupled to an increased understanding of the relationship between protein structure and function (Chapters 2 and 3) has facilitated the more recent introduction of several engineered therapeutic proteins (Table 1.3). Thus far, the vast majority of approved recombinant proteins have been produced in the bacterium E. coli, the yeast S. cerevisiae or in animal cell lines (most notably Chinese hamster ovary (CHO) cells or baby hamster kidney (BHK) cells. These production systems are discussed in Chapter 5. 

At least 1000 potential biopharmaceuticals are currently being evaluated in clinical trials, although the majority of these are in early stage trials. Vaccines and monoclonal antibody-based products represent the two biggest product categories. Regulatory factors (e.g. hormones and... 

In other cases, the widespread application of a biopharmaceutical may be hindered by the occurrence of relatively toxic side effects (as is the case with tumour necrosis factor a (TNF-a, Chapter 9). Finally, some biomolecules have been discovered and purified because of a characteristic biological activity that, subsequently, was found not to be the molecule s primary biological activity. TNF-a again serves as an example. It was first noted because of its cytotoxic effects on some cancer cell types in vitro. Subsequently, trials assessing its therapeutic application in cancer proved disappointing due not only to its toxic side effects, but also to its moderate, at best, cytotoxic effect on many cancer cell types in vivo. TNF s major biological activity in vivo is now known to be as a regulator of the inflammatory response. 

The presence of serum-binding proteins. Some biopharmaceuticals (including insulin-like growth factor (IGF), GH and certain cytokines) are notable in that the blood contains proteins that specifically bind them. Such binding proteins can function naturally as transporters or activators, and binding can affect characteristics such as serum elimination rates. 

The expression of recombinant proteins in cells in which they do not naturally occur is termed heterologous protein production (Chapter 3). The first biopharmaceutical produced by genetic engineering to gain marketing approval (in 1982) was recombinant human insulin (tradename Humulin ), produced in E. coli. An example of a more recently approved biopharmaceutical that is produced in E. coli is that of Kepivance, a recombinant keratinocyte growth factor used to treat oral mucositis (Chapter 10). Many additional examples are provided in subsequent chapters. 

Contaminant-clearance validation studies are of special signibcance in biopharmaceutical manufacture. As discussed in Section 7.6.4, downstream processing must be capable of removing contaminants such as viruses, DNA and endotoxin from the product steam. Contaminant-clearance validation studies normally entail spiking the raw material (from which the product is to be purihed) with a known level of the chosen contaminant and subjecting the contaminated material to the complete downstream processing protocol. This allows determination of the level of clearance of the contaminant achieved after each purihcation step, and the contaminant reduction factor for the overall process. 

Within the scope of biopharmaceutics and IVIVC, bootstrap techniques have been applied to several specific problems related to the estimation of confidence intervals of, e.g., the similarity factor/ (21), the Chinchilli metric (27), parameters of an open two-compartment system (32), and the SD in general (33). From these few applications, it cannot be judged how much is actually gained from these new techniques. 

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