Estimating the starting dose for entry into humans: principles and practice

Abstract.

Background: Selection of the starting dose for the entry into humans (EIH) study is an essential first step in clinical drug development. Objectives: This paper is a review of different approaches that may be used to calculate the starting dose, presents the results of a current practice survey that reflect practice patterns at a large pharmaceutical company, and discusses selected topics related to the calculation of the starting dose. Results: The methods used in the field of oncology for cytotoxic compounds are usually derived from a dose associated with some toxicity in animals multiplied by a safety factor. In therapeutic areas other than oncology, the methods may be classified as four different approaches: (1) dose by factor methods that utilize the no observable adverse effect level (NOAEL) from preclinical toxicology studies multiplied by a safety factor; (2) the similar drug approach that may be used when clinical data are available for another compound of the same chemical class as the investigational drug; (3) the pharmacokinetically guided approach that uses systemic exposure rather than dose for the extrapolation from animal to man; and (4) the comparative approach that consists of utilizing two or more methods to estimate a starting dose and then critically comparing the results to arrive at the optimal starting dose. A "real-life" example illustrates the use of each method. Advantages, limitations, and underlying assumptions of each of the methods are discussed. The results of the survey showed that the pharmacokinetically guided approach is the most commonly used method, followed by dose by factor methods. Conclusion: The task of estimating the starting dose is moving beyond empirical methods to those that are increasingly more systematic and theory based.