Pharmacokinetics and Pharmacodynamics Core

For a new chemical entity to be clinically useful, it must have, in addition to target selectivity, appropriate pharmacokinetic-pharmacodynamic properties.

Preclinical assessment of drug metabolism in both in vitro and in vivo systems, determination of biaoavailability, clearance and distribution in animal models together with concentration-response data for the parent drug as well as metabolites are used to make initial predictions for dose ranging Phase I studies, and to estimate expected inter-subject variability.

Phase I studies include both descriptive pharmacokinetics (levels of parent drug and metabolites as a function of time in plasma and excreta,) as well as calculation of pharmacokinetic parameters (clearance, bioavailability, volumes of distribution, distribution and elimination half-lives), their variability, and determination of whether kinetics are linear (and thus predictable) or dose-dependent within the presumed therapeutically relevant dose range. Combining pharmacokinetic information with dose/concentration-response curve characteristics permits the design of dosing regimens for phase II trials.

This core provides consultation in design and analysis of studies to determine pharmacokinetic characteristics and dose-response relationships of new therapeutic agents. For consultations and project development please contact Joseph Goldfarb at joseph.goldfarb@mssm.edu.

Pharmacokinetics and Pharmacodynamics: Animal Models

Pharmacokinetics [PKs] and pharmacodynamics [PDs] are key components in the drug discovery and development enterprise. The PK properties of a drug determine its concentrations in blood and tissues and the associated drug actions or PDs. As new drug molecules are discovered an evaluation of their suitability for use in humans has to be made, which ultimately requires a drug reaches and maintains therapeutic concentrations in the tissues or cells in which it elicits its desired action. When new drug entities are discovered investigators have to rely on preclinical investigations to determine the PK and PD characteristics since direct application to humans could have grave consequences in terms of toxicity, and also yield misinformation about the ultimate suitability of a drug candidate since how the drug should optimally be administered is unknown.

The preclinical investigations, using cells and rodent models, provide mechanistic insight into how drugs are absorbed, distributed, metabolized and eliminated from the body, and further can be used to predict such properties to humans. It is through a strong preclinical assessment of a drug's PK/PD properties that meaningful results can be translated into the clinic to rationally select and optimize drug usage.

The need for preclinical PK/PD investigations is readily appreciated when one considers the development of anticancer drugs that require penetration into tumors. Measurement of drug concentrations in a patient's tumor and the associated PD responses is a challenging exercise since many tumors are inaccessible, and even if a sample can be collected it has to be done on a limited basis, yielding incomplete information. However, in rodent tumors, drug concentration and PD measurements are readily available and provide significant insight into the underlying processes that control drug concentrations and responses in tumors. These tumor-based measurements allow the formulation of mathematical models that are tools to simulate drug behavior under different conditions and can serve as foundations to predict drug behavior in patient tumors. This quantitative basis of drug disposition and dynamics in tumors is a new PK/PD-directed drug development paradigm and seeks to evaluate new treatment strategies and translate significant findings into the clinic.

For consultations and project development please contact James M. Gallo at james.gallo@mssm.edu.