Design evaluation for a population pharmacokinetic study using clinical trial simulations: a case study.

Clinical trial simulations were conducted to assess power and sample size requirements for a population pharmacokinetic (PK) substudy of a phase III clinical trial. The simulations were based on a population PK model developed from phase I healthy volunteer data. A sparse sampling design was employed taking into account the practical considerations regarding the desire not to keep patients at the study sites for extended periods of time for blood sampling. It was expected that the sparse sampling design would not support fitting the same model developed in healthy volunteers due to the narrow range of sampling times. Therefore, a model with fewer parameters and variance components was fit to simulated data from the proposed design to assess the bias in the estimates of the population mean PK parameters and variance components. Results indicate that the proposed design employing the simple model can provide accurate mean estimates of oral drug clearance (CL) and the apparent steady-state volume of distribution (V(ss)). However, the simulation results also suggest that the size and power of the likelihood ratio test for subpopulation differences in CL are inflated when using the simple model. Copyright 2001 John Wiley & Sons, Ltd.