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. 2021 Feb 15:11:621667.
doi: 10.3389/fphar.2020.621667. eCollection 2020.

Estimation of the In Vivo Release of Amiodarone From the Pharmacokinetics of Its Active Metabolite and Correlation With Its In Vitro Release

Maytham Razaq Shleghm  1 , Constantin Mircioiu  1 , Victor A Voicu  1 , Ion Mircioiu  2 , Valentina Anuta  1
Affiliations

Estimation of the In Vivo Release of Amiodarone From the Pharmacokinetics of Its Active Metabolite and Correlation With Its In Vitro Release

Maytham Razaq Shleghm et al. Front Pharmacol. .

Abstract

Due to its very low water solubility and complex pharmacokinetics, a reliable point-to-point correlation of its in vitro release with its pharmacokinetics has not been achieved so far with amiodarone. The correlation of the in vitro 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 in vitro correlations in vivo, 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 in vivo dissolution is similar, after time scaling, to the dissolution measured experimentally in vitro. 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 in vitro-in vivo correlation, the problem became that of the correlation between in vitro dissolution time and in vivo 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 in vivo dissolution, t*, depended approximately linearly on the square root of the in vitro dissolution time t, with the two regression lines being practically parallel.

Keywords: amiodarone; desethylamiodarone; in vitro in vivo correlation; in vivo release; pharmacokinetics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Schematic representation of the main processes involved in the pharmacokinetics of AMD and its DAMD metabolite.
FIGURE 1
FIGURE 1
In vitro release data of AMD and modeling using the square law.
FIGURE 2
FIGURE 2
Plasma levels of DAMD.
FIGURE 3
FIGURE 3
Evaluation of the elimination part of plasma level curves: (A) linear representation and (B) logarithmic representation.
FIGURE 4
FIGURE 4
Dependence of FRAp(t) on time (A,B) and square root of time (C).
FIGURE 5
FIGURE 5
(A) FRA and FRD as functions of time scaled using a constant factor and (B) dependence of FRA of FRD.
FIGURE 6
FIGURE 6
Graphical presentation of the time scaling t–t* algorithm.
FIGURE 7
FIGURE 7
Dependence of t* on t (A), of square root of t (B).
FIGURE 8
FIGURE 8
Modeling the dependency t*(t) as a square root–type law for the reference drug, tested drug, and joint data.
See this image and copyright information in PMC

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