Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 31

Dose Ranging Crossover Designs

Scott D. Patterson, Byron Jones, and Névine Zariffa

31.1 Introduction

Why do we care about dose? Many people seemingly are of the opinion that “if a little is good, more is probably better.” However, this opinion is not necessarily the case in drug treatment. It is more complicated than that.

As illustrated by Sheiner and Steimer [1] and described in more detail in References 2 and 3, administration of a dose of drug results in exposure to drug at the site of action once drug enters the systemic circulation. At the site of action, drug molecules bind to receptors in the relevant organ, tissue, and so on, and hopefully cause a desired response, like lowering blood pressure, which improves how a patient feels, how long a patient lives, or some other desired clinical outcome.

Of course, once in the circulatory system, the drug may go to other sites than that desired and cause an undesired response. For example, consider the fatal example of terfenadine [4]. Doses of this drug resulted in cardiac arrythmia and death when given with a metabolic inhibitor. Experiences such as this have confirmed that a thorough understanding of how dose relates to response is critically important for a proper understanding of a drug’s usefulness (or lack thereof) [5–7].

An example in which response to dose can be monitored is in the use of a drug called warfarin. Such a drug is dangerous to use, but its use is said to prevent “twenty strokes for every episode ...