Scale up to humans

Kawai R, Mathew D, Tanaka C, Rowland M Physiologically based pharmacokinetics of cyclosporine A extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther 1998 Nov 287(2) 457-68. 

There are no general reliable methods to scale up from a mouse to a rat, and to a person nor is there a reliable method to scale down from a 70 kg male adult to an infant. A faster and less expensive toxicity test is the Ames test, performed on bacteria to test potentials for carcinogenesis, but the scale-up to humans is even more imprecise. 

Bonate, P.L., Swann, A., and Silverman, P.B. A preliminary physiological based pharmacokinetic model for cocaine in the rat Model development and scale-up to humans. Journal of Pharmaceutical Sciences 1996 85 878-883. 

Cancer now afflicts one out of four adults. One of the more promising therapies for certain kinds of cancers involves the use of interferon, a protein that occurs in minute quantities in the body where it is an essential part of the body s immune system. Interferon can be produced outside the body in cultures of transformed lymphoblastoid cells. A few years ago, it was possible to culture these human cells on scales up to a few hundred milliliters. Chemical engineers have now developed reactors for the aseptic culture of human cells on a scale 100,000 times larger, making it possible to produce human interferon in practical useful quantities. 

For these proteins, mammalian cells proved better hosts, as they could process the protein with intracellular machinery similar to that in humans. However, large-scale production of proteins in cell culture was problematic. Mammalian cells had to grow attached to a solid surface, such as glass in roller bottle culture. While the Federal Drug Administration (FDA) had approved some processes for vaccine production that used cell cultures, it required that these cells be normal. Normal mammalian cells can divide only a few times before they stop growing, making scale-up to large volumes difficult. 

Scale-up to 100-g quantities for animal testing, which must precede human studies, typically takes 3 to 8 months. Then, production must be scaled up to commercial quantities. Traditionally, the entire process takes 2 to 3 years—too long to be useful in a national emergency. 

Table 5.5.2 Scale-up of human hybridoma 4-8KH15 to the 12-1 stirred bioreactor ...

Clinical development continues with the application of the learn-confirm-learn paradigm applied to drug development. Scale up to the first-time-in-human (FTIH) study is best done by the application of sound PM methods as described by several authors (10, 51, 56). 

This method opened up both industrial production opportunities and allowed research laboratories to easily produce substantial quantities of developmental products. Microcarrier culture is the most versatile, reliable, and characterized procedure for unit volume scale-up of anchorage-dependent cells. It has had widespread use for industrial processes [vaccines, interferon, tPA, and human growth hormone (hGH)] as well as many developmental uses, has been scaled-up to 4000 L, and has the potential for process intensification by perfusion with spin filters or by the use of microporous microcarriers. 

This last concept has been extended to what is known as capillary array electrophoresis (CAE) (Huang et al., 1992 Kheterpal and Mathies, 1999), wherein there may be as many as 96 capillaries in parallel in instmments currently available (Zubritsky, 2002). This increases the throughput drastically. Such devices were the workhorse of the human genome analysis. Scaling up to 1000 capillaries has also been reported (Kheterpal and Mathies, 1999). Capillary array electrophoresis enables easy and parallel loading of multiple samples as well as rapid and parallel separation and detection using appropriate detection techniques. 

It is assumed that only healthy animals were used in the reviewed studies. Consequently, when scaling from smaller mammals up to humans, the derived estimate should correspond to a healthy human subpopulation. 

There are many criteria to examine when selecting a cell source for regenerative medicine. The cells should he readily available, easily differentiated into the cell type of interest, easily expanded for scale-up to the cell number needed for human therapies, have the potential for clinical translation (human cells from either an allogenic or autologous source), and have a low risk of unwanted differentiation (into nondesirable cell types) or proliferation after transplantation (after purification). However, no cell type currently available meets all of these criteria, so for now the risks and benefits of each cell type must be weighed for the desired application or research study. In this section, sources of stem cells for neurological injury and disorder will be discussed. 

A hallmark of PB-PK models is the ability to scale up animal-based models to humans, thus allowing tissue drug concentrations to be predicted in the absence of data that are difficult or impossible to collect. Initial efforts to apply interspecies extrapolations to anticancer drugs have been greatly extended to chemical risk assessment based on PB-PK models [14]. Empirical allometric equations based on animal body weight have been the mainstay to scale organ weights and... 

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