Effects of variability in hepatic clearance on the bioequivalence parameters of a drug and its metabolite: simulations using a pharmacostatistical model.

A semi-physiological pharmacostatistical model was developed and used to study the manner in which intra-individual variability in hepatic clearance is transmitted to the area-under the plasma concentration-time curve from zero to infinity (AUC) of a drug and its metabolite. In order to clarify the effects, the model contained no other sources of variability. As the drug's hepatic extraction ratio increased, the coefficient of variation (CV) of the AUC of the drug increased, whereas that of the metabolite decreased. The AUC of the metabolite increased as the drug's non-hepatic clearance increased. At high extraction ratios, the CV of the AUC of the drug was insensitive to the contributions of other forms of clearance. The results suggest that under certain circumstances, smaller samples sizes could be used in bioequivalence studies for highly variable drugs if the test were based on the metabolite rather than the parent drug.