Study Design

A single-dose, randomized, crossover design, is the most common choice for a dose-proportionality study. An incomplete block design, where an equal number of subjects are randomized to receive different doses and all cohorts together cover the full range of doses, is also an option. The latter design is occasionally employed when the total blood volume collected from a single volunteer would exceed standard limits of blood donations. The number of subjects participating in the study should be based on earlier studies where intersubject, and if available, intrasubject variabilities have been determined. Study drug should be administered with a standardized volume of water after overnight fast, and standardized meals should not be served until four hours post-dose.

Concomitant food intake should be avoided, unless the drug is associated with adverse events, such as nausea or vomiting, which could be circumvented by a small meal. It is advisable to include the rationale for coadministration of the drug and food in the protocol. If the drug is associated with adverse events that preclude high single doses, a titration design where the pharmacokinetics is determined at steady state can be an alternative.

In certain cases, a parallel-group design may be selected instead of a crossover design, e.g., for drugs with a long terminal half-life, although a substantially larger number of subjects may be needed compared to a crossover design. If a crossover design has been chosen, the investigational periods should be separated by an adequate washout interval (>5tV) to ensure that elimination is complete before a second dose is administered. Blood samples should be collected to adequately describe the full plasma/serum drug concentration profile, especially the terminal phase should be adequately described, where sampling should be continued up to at least three to four terminal tV of the drug and/or active metabolites.

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