Robust Procedures in Comparative Bioavailability Studies

Abstract

According to the current Food and Drug Administration (FDA) guideline, bioavailability is estimated based on the ratio of mean pharmacokinetic parameters (eg, area under the plasma concentration-time profile) of the test product to the reference product. This estimate may be markedly different from the central tendency of the individual ratios even if the parameter is normally distributed. Since an estimate of the location of individual bioavailability is more meaningful than the ratio of the mean pharmacokinetic parameter in many applications, there is a desire to study the individual ratios. Because the underlying distributions of individual subject ratios tend to be either skewed or heavy-tailed, two robust procedures are proposed to estimate bioavailability. The first approach is based on the M-estimator with a t-distribution weight function. It has been shown that this estimator is more efficient than a number of traditional and nonparametric estimators for a family of distributions with different shape parameters. For comparison purposes, another approach based on the sample median is also derived. A numerical example is provided to illustrate these procedures.