Abstract
For population pharmacokinetics in phase I trials, the standard two-stage (STS) method is quite appealing, especially to non-statisticians, because the method is theoretically and computationally simple. The method, however, does not take into account the uncertainty in estimating individual-specific parameters and gives biased estimates for population variances of pharmacokinetic parameters. This is one of the main reasons why the STS method is not generally recommended. This paper proposes a simple bootstrap modification of the STS method for estimating confidence intervals of population means and standard deviations of pharmacokinetic parameters in phase I trials. The proposed approach adopts a bootstrap bias correction in estimating population variances of pharmacokinetic parameters. Applications are given to a simulated data set and an actual phase I trial to show how the proposed approach works in practice.
Published Version
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