Pharmacodynamics PK-PD studies

Various hyphenated LC-MS-based assays, using either the electrospray ionization (ESI) or the atmospheric pressure chemical ionization (APCI) interface, have been developed and applied in the clinical setting in order to support pharmacokinetic (PK), pharmacogenetic-pharmacokinetic (PG-PK), and pharmacokinetic-pharmacodynamic (PK-PD) studies in BC patients under tamoxifen therapy (Table 3). 

Dose-escalation studies performed in an early phase of drug development provide preliminary information to explore pharmacodynamic parameters at different dose levels up to the MTD. If the focus of a study is on the relationship between the pharmacokinetic and pharmacodynamic parameters (rather than on dose response relationships), then the term PK PD studies is used. 

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. 

Therefore, this review of pharmacokinetic/pharmacodynamics (PK/PD) correlation will include investigations between the effective concentrations at the target sites of antisense oligonucleotides with each of the pharmacological effects discussed above. Moreover, an establishment of the correlation between plasma equilibrium concentrations with concentrations at the target sites is pertinent, enabling plasma concentrations to be used as a surrogate in clinical studies to establish relationships between pharmacodynamics and pharmacokinetics. 

To sum up, there is a great heterogeneity in the described methods that have so far been developed and, for the great majority of them, used in the clinical setting to support pharmacogenetic-pharmacokinetic-pharmacodynamic (PG-PK-PD) studies. Of these methods, only the most recent fully validated ones that have proven enough accuracy, precision, robustness, and selectivity seems to be reliable and suitable for measuring exposure of tamoxifen and its metabolites in tamoxifen-treated breast cancer patients. 

Human pharmacology (Phase I) Assess tolerance Define/describe pharmacokinetics and pharmacodynamics Explore drug metabolism and drug interactions Estimate activity Dose-tolerance studies Single and multiple dose PK and/or PD studies Drug interaction studies... 

The measurement of pharmacodynamics (PD) parameters in phase 1 studies can be very informative. First of all it may help to define the starting dose for subsequent studies in patients. It may also help to build a PK/PD model, which can be used as a framework for further development. 

This section deals with the question of whether there are quantitatively detectable and interpretable correlations between the dose of an administered drug, or the concentration of a drug and its metabolites measured in the blood or plasma (blood or plasma level), and the therapeutic action or side effects observed. Investigations relating to questions of this type are called PK PD (pharmacokinetic pharmacodynamic) studies. The PK PD analysis is a bidirectional approach pharmacokinetics represent what the body does with a drug, and pharmacodynamics describes what a drug does to the body. The PK PD analyses are key elements of early drug development, and PK PD trials are able to answer specific disease-related efficacy and safety questions. 

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