Estimation of the Release of Amiodarone From the Pharmacokinetics of Its Active Metabolite and Correlation With Its Release.

Due to its very low water solubility and complex pharmacokinetics, a reliable point-to-point correlation of its release with its pharmacokinetics has not been achieved so far with amiodarone. The correlation of the dissolution of a drug with the pharmacokinetics of one of its metabolites was recently proposed by the authors of the article as an additional or alternative analysis to the usual correlations , mainly in the case of fast-absorbing drugs that have metabolites with a significant therapeutic effect. The model proposed by the authors considers that amiodarone has a slow dissolution, rapid absorption, and rapid metabolism, and before returning to the blood from other compartments, its pharmacokinetics is determined mainly by the kinetics of release in the intestine from the pharmaceutical formulation. Under these conditions, the rate of apparition of desethylamiodarone in the blood is a metric of the release of amiodarone in the intestinal fluid. Furthermore, it has been shown that such an estimated dissolution is similar, after time scaling, to the dissolution measured experimentally . Dissolution data of amiodarone and the pharmacokinetic data of its active metabolite desethylamiodarone were obtained in a bioequivalence study of 24 healthy volunteers. The elimination constant of the metabolite from plasma was estimated as the slope of the linear regression of logarithmically transformed data on the tail of plasma levels. Because the elimination of desethylamiodarone was shown to follow a monoexponential model, a Nelson-Wagner-type mass equilibrium model could be applied to calculate the time course of the "plasma metabolite fraction." After Levi-type time scaling for imposing the correlation, the problem became that of the correlation between dissolution time and dissolution time, which was proven to follow a square root model. To validate the model, evaluations were performed for the reference drug and test drug separately. In both cases, the scaled time for dissolution, , depended approximately linearly on the square root of the dissolution time , with the two regression lines being practically parallel.