In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of Its Metabolite

Mircioiu, Constantin; Anuța, Valentina; Mircioiu, Ion; Nicolescu, Adrian C.; Fotaki, Nikoletta

doi:10.3390/pharmaceutics11070344

Cited by 20 publications

(15 citation statements)

References 28 publications

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“…In the past, limited success has been achieved in the field of IVIVC with passionate investigation efforts [19][20][21][22]. One explanation for this restricted achievement was due to the poor in vivo predictivity of the traditional in vitro dissolution methods.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

Liu

Zhang

et al. 2021

Journal of Nanomaterials

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The present study evaluated the ability of a modified flow-through method for predicting in vivo performance of immediate release (IR) and extended release (ER) formulations. In vitro dissolution of two model drugs, paracetamol IR tablets and felodipine ER tablets, was investigated under tuned conditions using the modified flow-through method and compared with the compendial quality control (QC) basket method. The in vivo absorption properties of paracetamol IR tablets and felodipine ER tablets were investigated in healthy volunteers. In vitro-in vivo correlation (IVIVC) analysis was performed based on the obtained in vitro and in vivo data. Our results demonstrated that the compendial QC method was not able to reflect in vivo actual absorption, while satisfactory discriminatory power and comparable in vitro dissolution/in vivo absorption were achieved for both paracetamol IR tablets and felodipine ER tablets by the modified flow-through method. This study indicated that the modified flow-through method is a potential tool to reflect in vivo performance of the IR and ER formulations.

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Section: Introductionmentioning

confidence: 99%

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

Liu

Zhang

et al. 2021

Journal of Nanomaterials

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“…Another interesting aspect revealed was that alverine parent accounts for only 3%, whereas total 4-hydroxy alverine (free and conjugated) accounts for about 94% of alverine-related moieties in circulation (based on comparisons of total exposure). This finding would strongly suggest that the research and development program for future generic alverine formulations would benefit from integrating pharmacokinetic metabolite data in both IVIVC (Savu et al, 2016;Mircioiu et al, 2019) and in vivo bioequivalence testing models.…”

Section: Discussionmentioning

confidence: 99%

Single Dose Study Assessing the Pharmacokinetic and Metabolic Profile of Alverine Citrate in Healthy Volunteers

2021

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Alverine citrate is a spasmolytic commonly prescribed in conditions such as irritable bowel syndrome, painful diverticular disease of the colon, and primary dysmenorrhea. While clinical efficacy data on alverine alone or in combination with simethicone is freely available, surprisingly little information regarding the pharmacokinetics and metabolism of alverine can be found in literature. The first HPLC-MS/MS analytical protocol for determination of alverine parent, 4-hydroxy alverine, N-desethyl alverine and 4-hydroxy alverine glucuronide in human plasma was developed and validated. The two validated methods were used for analyzing plasma samples collected during an open label, non-comparative, single dose, one-period, one-treatment, pharmacokinetic and metabolic profile study of Spasmonal® Forte 120 mg hard capsule, conducted in 12 fasting healthy male and female volunteers of Caucasian descent. The study confirmed previous suspicions that parent alverine is subject to high pharmacokinetic variability and also revealed that the metabolic process most susceptible to outlying performance in Caucasians is hydroxylation to the active metabolite 4-hydroxy alverine. Another interesting observation made is that alverine parent accounts for only 3%, whereas total 4-hydroxy alverine (free and conjugated) accounts for 94% of alverine-related moieties in circulation (based on comparisons of total exposure).

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“…The hypothesis of this article, presented previously by the authors ( Mircioiu et al, 2019a ), was that if the absorption and metabolism can be assumed to be rapid, then the apparition of metabolite in plasma

( t ) could be considered an estimation of the absorption of the parent drug from the intestine FRA ( t i ). Based on this hypothesis, a correlation between in vitro dissolution and the in vivo pharmacokinetics of metabolites would be expected, which was indeed found in the case of diltiazem.…”

Section: Methodsmentioning

confidence: 99%

“…A modified, Wagner–Nelson-type equation ( Mircioiu et al, 2019a ) was applied for the calculation of the “fraction of apparition” in plasma of the metabolite ( FRAp ):

where FRAp DAMD is the fraction of the apparition of the metabolized drug at time t i , c dAMD ( t i ) is the plasma concentration of the metabolite at time t i , and

denotes the apparent elimination rate constant.…”

Section: Methodsmentioning

confidence: 99%

“…The present article attempts to apply a recent method ( Mircioiu et al, 2019a ) of correlation between the dissolution of the parent drug and the pharmacokinetics of one of its metabolites, to the correlation between the in vitro dissolution of amiodarone and the rate of plasma desethyl active metabolite of amiodarone, based on data from a bioequivalence study.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of Its Metabolite

Cited by 20 publications

References 28 publications

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

Single Dose Study Assessing the Pharmacokinetic and Metabolic Profile of Alverine Citrate in Healthy Volunteers

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

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