Selection of doses for phase II clinical trials based on pharmacokinetic variability consideration.

ABSTRACT

Pharmacokinetic variability is an important component of the total variability in drug response, but Phase II dose-response trials frequently are designed without considering this important factor. Mixed-effects model simulation was performed to examine overlap of patient area under the concentration-time curve (AUC) values between doses for drugs with differing inter- and intrapatient pharmacokinetic variability. Based on the results of this simulation, a dose increment of at least threefold is needed to ensure that drug exposure does not overlap in at least 50% of the patient population for a drug that exhibits greater than 25% variability. In contrast, an increment factor of 2 is normally sufficient to produce the same degree of resolution when the variability is less than 25%. These results suggest that a more aggressive choice of administration increments could lead to a better separation in systemic drug exposure between doses. This needs to be balanced against the therapeutic window of an individual drug product.