Role of metabolites for drugs that undergo nonlinear first-pass effect: impact on bioequivalency assessment using single-dose simulations.

We investigated the effects of dose and intrasubject variability (ISV) on bioequivalence (BE) of a parent drug with a single metabolite formed by nonlinear first-pass. A BE simulation was done using a four-compartment model at doses of 17.5, 35.0, and 70.0 mg. ISV was set at either 10% or 20% for clearance and either 20% or 50% for the absorption rate constant, K(a). The ratio of Katest/Kreference was fixed at 1.00 while fraction available ratios, F(test)/F(reference), were varied from 1.00 to 1.25. Results showed the probability of passing the 90% confidence interval (CI) BE requirement for AUC(I), area-under-the-concentration curve to time infinity, and C(max), concentration maximum, were greater for the metabolite than the parent at all F(test)/F(reference) ratios. For the parent, the probability of meeting BE criteria for AUC(I) and C(max) declined from 100% to 60% at the 70 mg dose as the ISV for K(a) increased from 20% to 50% with an increased F(test)/F(reference) ratio. For the metabolite, the probability of meeting BE criteria was above 80% for all doses and ISV values and F(test)/F(reference) ratios less than 1.15. Results show that the parent, reflected absorption, is more informative for determining BE than the metabolite. Clinical data gave a similar result.