Computer simulations of bioequivalence trials: Selection of design and analyte in BCS drugs with first-pass hepatic metabolism: Linear kinetics (I)

Modeling and simulation approaches are useful tools to assess the potential outcome of different scenarios in bioequivalence studies. The aim of this study is to propose a new and improved semi-physiological model for bioequivalence trial simulations and apply it for all BCS (Biopharmaceutic Classification System) drug classes with non-saturated first-pass hepatic metabolism. The semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Parent drug and metabolite levels for both reference and test were simulated. Eight types of drugs (with high or low permeability and high or low solubility (class I to IV) and high or low intrinsic clearance) were considered in two variability scenarios (high-low) and in six test products of decreasing biopharmaceutic quality. The scenarios were tested in single dose and steady state studies. In case of drugs with non-saturated hepatic first-pass effect (and no gut-wall metabolism) the parent drug is usually the most sensitive analyte and the single dose design is usually the most sensitive study design to detect the worsening of the biopharmaceutic quality of the test formulation. The only exception to this general conclusion was observed in class III drugs (high solubility, low permeability) with low intrinsic clearance for which the parent drug Cmax ratio in steady state shows higher sensitivity followed by the metabolite Cmax ratio in single dose. This exceptional behaviour is caused by a limited operative absorption time (or absorption window) in class III drugs that precludes complete absorption and produces a non-linear absorption. Therefore, it can be concluded that the metabolite does not need to be measured if the drug has no gut-wall metabolism and shows linear pharmacokinetics. Interestingly, a steady state study should be conducted in this exceptional case to compare with the highest possible sensitivity. Metabolite data in most of the scenarios either shows less sensitivity to the product characteristics (resulting in Cmax ratios passing the bioequivalence criteria when the products were not bioequivalent) or it gives the same information as the parent compound.