The role of metabolites in bioequivalency assessment. I. Linear pharmacokinetics without first-pass effect.

The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using Cmax of parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of Cmax values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for Cmax of the metabolite and, in turn, a tighter confidence interval for Cmax of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for Cmax of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.