Utility of Pilot Studies for Predicting Ratios and Intrasubject Variability in High-Variability Drugs

Abstract

Pilot studies can be used to identify adequate test formulations for pivotal bioequivalence trials. The objective of this study was to evaluate the usefulness of pilot studies in predicting ratios and the intrasubject coefficient of variation (CVw) for pivotal studies of high-variability drugs. Seven cross-over and replicate bioequivalence trials were selected. A hundred simulations of pilot studies were performed for different sample sizes and designs. The pharmacokinetic data of the selected formulations were analysed using WinNonLin based on an analysis of variance (anova). The CVw was estimated using the formula recommended by the European Medicines Agency based on the mean square of the anova. We calculated the predictivity index ± 10% and ± 20% of the real value. The predictivity index of ± 20% in the 2 × 2 design with 12 volunteers was 100% for AUC0–t ratio, 87% for Cmax ratio, 50% for the CVw of AUC0–t and 52% for the CVw of Cmax. The results of the 4 × 4 design with 8 volunteers were similar to those of the 2 × 2 design with 12 volunteers. These results were worse for the predictivity index of ± 10% in both designs. Pilot studies do not seem useful for predicting sample size. However, they were very good for predicting the AUC0–t ratio and good for predicting the Cmax ratio. The most adequate design for pilot studies seems to be the 2 × 2 design with at least 12 volunteers.