Selection of doses for phase II clinical trials based on pharmacokinetic variability consideration.
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.
Yu
D K
DK
Hoechst Marion Roussel, Inc., Kansas City, Missouri 64137, USA.
Bhargava
V O
VO
Weir
S J
SJ
D019540:Area Under Curve; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D006801:Humans; D008962:Models, Theoretical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010599:Pharmacokinetics
D004364:Pharmaceutical Preparations