Animal models dosing regimens

During product development, many of the initial non-clinical studies were undertaken in GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal model for Pompe s disease. The mice proved useful in assessing the pharmacodynamic effect of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its administration at clinically relevant doses. 

As the basis for decisions about the first dosing in humans, the preclinical safety program needs to mimic the intended clinical regimen. Although these studies are commonly conducted in normal healthy animals, they may also require development and use of an animal model that mimics the health status or condition if it is deemed to possibly sensitize the subject to treatment. For example, we have conducted studies evaluating the safety of recombinant human Factor XIII in an animal model of extracorporeal blood circulation [6] and the safety of recombinant human thrombin in an animal model of hepatic resection [7]. 

Several animal model studies have focused on the immime response to infection and also to vaccination. Most studies identify antibody titer, but some also show cytokine production or possible mechanisms of bacterial evasion. A focus on immime response studies will help to further define B. anthracis pathogenesis and provide insight into the design of future vaccines and therapeutics. Most countermeasure studies have been conducted on vaccines, as antibiotic studies have typically been performed in vitro. Primary concerns are the length of required treatment, effieient prophylaxis methods, and less complicated dosing regimens for vaccines. In a theoretical bioterrorist attack scenario, it will be essential to distribute effective treatment and prophylaxis to infected or potentially exposed persons in an expedient manner. 

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