Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics.
Eur J Pharm Sci
; 174: 106198, 2022 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-35504449
ABSTRACT
AIMS:
The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations.METHODS:
Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4.RESULTS:
The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen.CONCLUSIONS:
The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.Palavras-chave
95%ci, confidence intervals 95%; Abbreviations: -2ll, -2xlog(likelihood); Am, amiodarone; Amiodarone; Enterohepatic recirculation; Gof, goodness of fit; Her, entero-hepatic reabsorption; Iiv, inter-individual variability; Iv, intravenous; OFV, objective function value; OR, oral; Oral formulation; PK, pharmacokinetics; Pharmacometrics; Polysorbate 80; Population pharmacokinetic modeling; Protein binding; RUV, residual unexplained variability; pc-VPC, prediction-corrected visual predictive checks
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Amiodarona
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article