Regulatory submissions pharmacokinetics

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Projection and application Examine the usefulness of the popnlation pharmacokinetic model to describe pharmacokinetic and relevant covariate relationships for regulatory submission or query, answer real-world questions about the data, and propose additional studies based on findings. 

Outside the EEC, the Swiss regulatory agency (Interkantonale Kon-trollstelle fur Heilmittel) has issued a brief statement on its approach to evaluating submissions on chiral drugs. The Swiss state that, for a mixture of isomers, data for each component should be available on the respective pharmacodynamics, pharmacokinetics, toxicity, and metabolism. Pharmacokinetic data, based on nonspecific analytical methods, wiU be assessed very critically. For pure isomers, other isomers, if present, are regarded as impurities. A new application fora pure isomer of a substance that is already registered as a racemate will be treated as an NCE application. 

Pharmacokinetic/pharmacodynamic modeling plays an important role during the NDA submission and review phase by integrating information from the pre-clinical and development phases. Existence of a well-defined PK/PD model furthermore enables the reviewer to perform PK/PD simulations for various scenarios. This ability helps the reviewer gain a deeper understanding of the compound and provides a quantitative basis for dose selection. Thus, PK/PD modeling can facilitate the NDA review process and help resolve regulatory issues. ... 

This chapter will focus on the current state of knowledge with regard to DNA-based differences in pharmacokinetics and pharmacodynamics of medications. It will provide an update on how the pharmacogenomic information is being applied and reviewed in IND and NDA submissions and provide examples of when voluntary submissions may be appropriate. Critical issues in the regulatory review and labeling implications of pharmacogenomic data will be also discussed. 

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