Computer simulations for bioequivalence trials: selection of analyte in BCS drugs with first-pass metabolism and two metabolic pathways.

The objective of this work is to use a computer simulation approach to define the most sensitive analyte for in vivo bioequivalence studies of all types of Biopharmaceutics Classification System (BCS) drugs undergoing first-pass hepatic metabolism with two metabolic pathways. A semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Four BCS classes (from Class I to IV) of drugs, with three possible saturation scenarios (non-saturation, saturation and saturation of only the major route of metabolism), two (high or low) dose schemes, and six types of pharmaceutical quality for the drug products were simulated. The number of investigated scenarios was 144 (4 × 3 × 2 × 6). The parent drug is the most sensitive analyte for bioequivalence trials in all the studied scenarios. Metabolite data does not show sensitivity to detect differences in pharmaceutical quality or it gives the same information as the parent compound. An interesting point to notice is the case of class I drugs administered at a high dose when the principal metabolic route is saturated and the secondary one is not saturated. In this case a substantial reduction in dissolution rate (as it could occur in the case of a prolonged release formulation developed as a line extension of an immediate release formulation) leads to a considerable increase in the AUC of the major metabolite whose formation is saturated supporting the need to require pharmacokinetic and clinical data for new prolonged release medicinal products.