Biopharmaceuticals dose-response

Since risk analysis plays an important role in public policy decision making, efforts have been made to devise a means by which to identify, control, and communicate the risks imposed by agricultural biotechnology. A paradigm of environmental risk assessment was first introduced in the United States by Peterson and Arntzen in 2004. In this risk assessment, a number of assumptions and uncertainties were considered and presented. These include (1) problem formulation, (2) hazard identihcation, (3) dose-response relationships, (4) exposure assessment, and (5) risk characterization. Risk assessment of plant-made pharmaceuticals must be reviewed on a case-by-case basis because the plants used to produce proteins each have different risks associated with them. Many plant-derived biopharmaceuticals will challenge our ability to define an environmental hazard (Howard and Donnelly, 2004). For example, the expression of a bovine-specihc antigen produced in a potato plant and used orally in veterinary medicine would have a dramatically different set of criteria for assessment of risk than, as another example, the expression of a neutralizing nonspecihc oral antibody developed in maize to suppress Campylobacter jejuni in chickens (Peterson and Arntzen, 2004 Kirk et al., 2005). 

The dose-response relationship for each biopharmaceutical can be analyzed, and the variation between subjects in the study population can be derived. A representative curve, presented as drug concentration versus effect intensity, is shown in Figure 5.8. It indicates that variation exists in intensity at a given drug concentration and in drug concentration at a given level of intensity. The steepness or slope of the... 

Gabrielsson, J., Jusko, W., and Alari, L., Modeling of dose-response-time data Four examples of estimating the turnover parameters and generating kinetic functions from response profiles, Biopharmaceutics Drug Disposition, Vol. 21, No. 2, 2000, pp. 41-52. 

Fu H, Price K, Nilsson M, and Ruberg S. 2013. Identifying potential adverse events dose-response relationships via Bayesian indirect and mixed treatment comparison models. Journal of Biopharmaceutical Statistics 23 26-42. 

Nabi has successfully completed several phase II studies for NicVAX. The results from a phase Ilb dose-ranging study in 301 heavy smokers showed that a significantly greater number of vaccinated participants met abstinence endpoints compared to placebo. Furthermore, vaccinated participants who successfully achieved abstinence were shown to have a higher level of antibody response than those vaccinated participants who did not achieve abstinence (Nabi Biopharmaceuticals 2007). Nabi is expected to start phase III trials this year. 

The induction of antibody formation against biopharmaceuticals in animal test species is not highly predictive for the potential of antibody formation in humans. Humans may also develop antibodies to human or humanized proteins that may not necessarily abrogate a therapeutic response. However, in repeat-dose safety animal studies with a biopharmaceutical, it is imperative that the sponsor (developer) establish that any antibody response detected does not neutralize the biopharmceutical or significantly alter its clearance or the animal s exposure. Product sponsors should modify the interpretation of safety results to account for any such attenuation of exposure. In general, biopharmaceuticals given by an intravenous route can be expected to be less antigenic than those administered subcutaneously. 

Four-week toxicology studies in rodent and nonrodent The four-week studies are designed for subchronic exposure of rodents and nonrodents to the test article. These studies also look at reversibility of any toxicity observed. Many times these are the pivotal studies used to support the first in human dosing. Toxicokinetic assessments are generally included in repeat-dose toxicity studies. When testing biopharmaceuticals, studies also include assessment and characterization of immune response (immunogenicity). 

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