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CHAPTER OBJECTIVES

  • To provide a description of the drug development process in the context of PK/PD studies.

  • To highlight the main types of regulatory submission pathways and details what is specific to the United States, the European Union, and Canada.

  • To give an overview of the critical PK information that is to be presented in the label and/or monograph after appropriately conducting PK/PD study.

  • To describe the importance of the relative bioavailability of a drug depending on the different routes of administration.

  • To specify the impact of PK nonlinearity on dosing regimen adjustments.

  • To describe the objectives of an appropriately conducted single ascending dose (SAD) study and how it relates to multiple ascending dose (MAD) study.

  • To describe the objectives of an appropriately conducted SAD study.

  • To explain why food effect studies are usually conducted with a high-fat high-calorie breakfast.

  • To describe the objectives of a mass balance study.

  • To define the relationship between drug clearance, renal clearance, and non-renal clearance in a renal impairment study.

  • To describe the importance of measuring unbound concentrations in a liver impairment study.

  • To describe the design of a drug–drug interaction study with consideration to induction, irreversible inhibition, or reversible inhibition.

  • To describe the importance of assessing QT prolongation for new drug products.

  • To describe the importance of conducting population PK/PD studies in all stages of the drug development process.

  • To provide a description on how to step-by-step validate a population PK model.

INTRODUCTION

We have seen throughout the previous chapters that the relationship between pharmacokinetics (PK) and pharmacodynamics (PD) (efficacy and safety) is a fundamental principle of clinical pharmacology. Understanding the PK/PD of a new drug or biological product is therefore essential to its development and to ensure its safe and effective use on the market.

We will see in this chapter what are the necessary requirements in terms of PK/PD that a pharmaceutical company must address for a new drug submission, so that clinicians can better understand how study results relate to the official drug label or monograph.

OVERVIEW OF THE DRUG DEVELOPMENT PROCESS

The drug development process is planned in different stages, starting with the discovery of new drug molecules and biologics, followed by preclinical1 testing, initial human (Phase I) studies, followed by clinical safety and efficacy (Phase II and Phase III) studies.

An essential part of drug development is the characterization of the PK and PD of the new drug product and the relationship of PK and PD to safety and efficacy. Estimating, understanding, and predicting the PK and PK/PD of a drug product is an essential part of drug development.

Physiologically-based PK (PBPK) models are more commonly used in the discovery phase and nonclinical stages of new molecules in order to better select candidates for preclinical studies. The results of the PBPK studies aid in ...

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