Key result
Polysorbate 80-formulated amiodarone boosts oral bioavailability by ~35% versus standard tablets in rats.
Why the study?
To characterize the absorption properties of oral amiodarone formulations at different doses and evaluate the impact of entero-hepatic circulation on its time-course in rats to optimize new oral formulation development.
Absolute Event Rate: 50% vs 37%
Formulating amiodarone with supramicellar concentrations of Polysorbate 80 enhances its absorption rate and bioavailability in a rat model.
May warrant human pharmacokinetic trials; leaves open clinical translation of Polysorbate 80-amiodarone formulations.
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: 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.
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Rodríguez-Fernández et al. (2022) studied Pharmacokinetics of amiodarone (n=96). Amiodarone oral formulations (Solution I, Solution II, Tablet) vs. Intravenous amiodarone formulation was evaluated on Oral bioavailability. Amiodarone formulated with supramicellar concentrations of Polysorbate 80 (Solution II) increased oral bioavailability to 50% compared to 37% for the tablet formulation in rats.
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