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CHAPTER OBJECTIVES

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  • Quantitatively describe the relationship between drug, receptor, and the pharmacologic response.

  • Explain why the intensity of the pharmacologic response increases with drug concentrations and/or dose up to a maximum response.

  • Explain the difference between an agonist, a partial agonist, and an antagonist.

  • Describe the difference between a reversible and a nonreversible pharmacologic response.

  • Define the term biomarker and explain how biomarkers may be used in the clinical development of drugs.

  • Show how the Emax and sigmoidal Emax model describe the relationship of the pharmacodynamic response to drug concentration.

  • Define the term pharmacokinetic–pharmacodynamic model and provide equations that quantitatively simulates the time course of drug action.

  • Explain the effect compartment in the pharmacodynamic model and name the underlying assumptions.

  • Describe the effect of changing drug dose and/or drug elimination half-life on the duration of drug response.

  • Describe how observed drug tolerance or unusual hysteresis-type drug response may be explained using PD models based on simple drug receptor theory.

  • Define the term drug exposure and explain how it is used to improve drug therapy and safety.

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PHARMACOKINETICS AND PHARMACODYNAMICS

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The role of pharmacokinetics (PK) to derived dosing regimens to achieve therapeutic drug concentrations for optimal safety and efficacy will be discussed in the next two chapters. A more objective approach for designing a drug’s dosing regimen would need to link the exposure of the drug within the body to the desirable (efficacy) and undesirable (safety/toxicity) effects of the drug. At the site of action, the drug interacts with a receptor that may be located within a cell or on special cell membranes. This drug–receptor interaction initiates a cascade of events resulting in a pharmacodynamic response or effect. Thus, pharmacodynamics (PD) refers to the relationship between drug concentration at the site of action (receptor) and the observed pharmacologic response. This chapter describes how the exposure of a drug over time (dose, concentrations, dosing regimens) can be related to the desirable and undesirable effects of the drug. Just as the PK of a drug has been described via mathematical models such as a one- or two-compartmental model, the relationship between drug concentration and effect can also be described using mathematical models. These PK-PD models can further be applied for simulations and prediction of drug action. This chapter is organized as follows: First, formal definitions of terms and those used interchangeably in the PK-PD literature are provided. Second, an introduction to how the PK-PD principles are integrated into drug development is provided. In addition, the chapter briefly describes the drug receptor theory and the use of biomarkers. This is followed by the theoretical basis of PK-PD relationship. Lastly, the chapter describes the different types of possible PK-PD relationships showing how the time course of drug action relates to drug concentration in the body. Examples and case studies are provided in the chapter to integrate therapeutic concepts and drug development perspectives.

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Definitions for Exposure, Response, ...

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