Pharmacokinetics animal disease models

RNAi has had an important impact on the development of novel disease models in animals, and it is likely that siRNAs, the trigger molecules for RNA silencing, will become an invaluable tool for the treatment of genetic disorders. The rational design of siRNAs, the introduction of chemical modifications into siRNAs to improve their pharmacokinetic and pharmacodynamic properties for in vivo application with high specificity, and the development of efficient delivery system will foster the therapeutic application of RNAi in AD and other neurodegenerative disorders (413,417). 

A solution to this difficulty would be to define the depletion profile in clinical subjects or in disease models that closely simulate clinical disease. No attempt is made to meet this ideal for a range of ethical, economic, and scientific reasons. Instead, reliance is placed on conducting residue (like pharmacokinetic) studies in healthy animals. This is justified by the series of conservative assumptions made in establishing withholding periods (see Section... 

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. 

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

In addition to toxicity and safety data, the preclini-cal package to start clinical studies also contains information on the pharmacology, the pharmacokinetics and metabolism and the galenical aspects of the compound. As a rule there is evidence of pharmacological activity and, if possible, of therapeutic activity in one or more animal models of disease. Ideally there is also information on the in vivo concentration effect relationship. 

The primary objective of the early efLcacy studies is to validate the pharmacology model with a compound that is known to interact with the desired receptor and develop the Pharmacokinetics-Pharmacodynamics (PK-PD) relationship for further screening during lead optimization (Neervan-nan, 2006). It is essential that the excipients selected forthe vehicle do not interfere with the measured end points especially, for a disease-relevant animal model that has no clinically effective drugs to validate an animal model. In this situation, vehicles should be used as negative controls in the studies. 

A series of pharmacokinetic and ADME studies was performed with imi-glucerase in order to assess clearance and targeting of imiglucerase in vivo. Because there was no suitable animal model for Gaucher disease, these studies were performed in normal animals. 

These animal models of disease should be considered early on as potentially providing some of the data necessary for initiation of human studies. Besides utility as proof of concept, they can add to understanding dose response as well as help evaluate some safety endpoints. New products resulting from improved manufacturing can be compared with previously produced material using pharmacokinetic parameters. 

Levy and others (35,36) have developed an extensive literature which demonstrates in animal models of disease that the pharmacodynamics of a number of drugs are altered, even after controlling for pharmacokinetic changes. Studies with drugs administered as racemic mixtures in humans with renal dysfunction, hepatic dysfunction, and other disease states that address the issue of stereoselective pharmacodynamics are lacking. However, the cited animal studies suggest that such a line of investigation would be fruitful. 

Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. Journal of Infectious Diseases 158 831-847... 

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