Pharmacodynamics toxicology studies

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

In conclusion, the ability to define the dosages of a protein scaffold therapeutic to be used in toxicology studies may prove to be difficult. Because the potential exists for these compounds to produce minimal toxicity, the dose selection process may rely more heavily on exaggerated pharmacodynamic effects than traditional small molecules have historically used. 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

The mid and low doses for a carcinogenicity study are to provide information for assessing the relevance of the study findings to humans. The low dose should be equal to, or a multiple of, the maximum dose proposed for human testing. The rationale for the selection of the low and mid dose needs to be provided on the basis of pharmacokinetic linearity and saturation of metabolic pathways, human exposure and therapeutic dose, pharmacodynamic response in the test species, alteration in the normal physiology of the test species, mechanistic information and the potential for threshold effects, and the unpredictability of toxicity progression observed in other toxicology studies. 

Finally, validation of the target pathway by discovery biologists is an excellent opportunity to consider the viability of potential biomarkers of intended pharmacodynamic activity. Biomarkers can be applied in toxicology studies to refine the dosimetry of adverse effects and to help guide clinical dosing. The application of biomarkers as an adjunct to toxicology testing is also discussed later in this chapter. 

Clinical trial protocols and a review on pharmacodynamic and toxicological studies to be sent to clinical investigators... 

The uses and limitations of toxicology, pharmacokinetic (PK) and pharmacodynamic (PD) studies. It is important to study biological activity in vitro and/or in vivo in a pharmacologically relevant animal species. The use of an animal model which potentially mimics the pathophysiology/symptoms of the clinical disease is preferred. 

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