Pharmacokinetic studies paradigm

The toxicity to the nervous system depends on the delivered dose and exposiue duration. In the case of pregnant women, pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern PAH disposition within the mother and the nervous system of children. Moreover, unique physiological features, such as the presence of a placental barrier and the gradual development of the blood-brain barrier influence PAH disposition and thus modulate developmental neurotoxicity. Because CNS effects are dependent upon windows of susceptibility when the lowest dose and shortest duration of exposure to environmental PAHs will have the greatest negative impact on brain development, a susceptibility exposure paradigm has proven to be the most reliable model in which to study developmental insult. The intent of this chapter was to review... 

The paradigm in drug development is sequentially divided into several phases starting with preclinical assessment. After selection of a drug candidate based on preclinical studies, clinical Phase 1 studies are initiated to characterize the safety, tolerability, biomarker, and pharmacokinetic profiles of the candidate, typically in healthy subjects. Phase 2 studies test the drug efficacy hypothesis in patients and explore dose range, and Phase 3 studies aim to demonstrate efficacy in the intended patient population in a statistically robust manner. 

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