Karine Rodriguez-Fernandez (1), E Gras (2), M Climente-Martà (3,4), V Mangas-Sanjuán(1,5), M Merino-Sanjuan (1,5)
(1) Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia. Valencia, Spain. (2) Department of Pharmacy, Hospital Manises of Valencia, Spain. (3) Department of Pharmacy, University Hospital Doctor Peset of Valencia, Spain. (4) Foundation for the Promotion of Healthcare and Biomedical Research in the Valencian Community (FISABIO), Valencia, Spain. (5) Interuniversity Research Institute for Molecular Recognition and Technological Development, Polytechnic University of Valencia-University of Valencia. Valencia, Spain.
Background: Amiodarone (AM) is a class III antiarrhythmic drug in the treatment of life-threatening ventricular and supraventricular arrhythmias. Commercially available amiodarone presentations include intravenous (IV) and oral (OR) administrations. OR administration is indicated in patients with mild and moderate heart disease, whereas IV is preferred in advanced structural heart disease patients. AM has been classified as a narrow therapeutic drug, which shows high lipophilicity in plasma and depot tissues due to the extreme affinity to lipids [1], which can explain their considerable side effects. In this sense, new technological strategies have been proposed to improve the pharmacokinetic (PK) properties of amiodarone and, with it, its safety profile [2]. However, the absorption properties of AM are uncertain with a low and variable bioavailability after OR administration.
Objectives: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels and routes of administrations, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of AM in rats in order to optimize the development of new OR formulations of AM.
Methods: The experimental dataset consisted of 164 20-weeks 250-320 g of body weight old male Wistar rats including 1,631 AM observations of AM in plasma (n=1,547) and bile (n=84). IV formulations consisted on a solution of a commercial injectable of AM clorhidrate (Trangorex ®, 150 mg/ml). Three OR formulations were evaluated, which included an oral solution from the commercial injectable of AM (Solution), the OR administration of AM through tablets (suspension) and an OR aqueous solution of AM clorhydrate with surfactant Tween 80 ® at 5% (supramicellar solution). The dose levels selected were 12.5 mg (IV), 10 mg (OR), and 25 mg (OR). Equal PK parametrization of the disposition of AM was assumed as described by Campos-Moreno et al. [1]. Inter-individual variability (IIV) associated to the PK parameters was modeled exponentially and residual unexplained variability (RUV) was described with an additive model on the logarithmic scale. The population PK parameters were estimated using SAEM+IMP. Model selection was based on the statistically decrease of the OFV and the GOF plots. Model evaluation was performed through pc-VPC and bootstrap analysis (n=1000). Experimental data were logarithmically transformed. All data analyses were performed based on the population approach with the software NONMEM v7.4.
Results: The absorption process after the OR administration of three formulations of AM (solution, suspension, and supramicellar Tween80®solution) were described through a linear process using different first order rate absorption constants for each formulation (ka1-3). The results suggest a major improvement in the absorption of AM when formulated as solution in the presence of Tween 80® (54% increase in ka) compared to suspension from tablets (38% reduction in ka). AM showed a moderate OR bioavailability, which was parametrized independently for each formulation. Suspension from tablets showed less OR bioavailability (37%), compared to oral AM solution (40%) and oral AM supramicellar solution (50%). The PK disposition model of AM was expanded by incorporating ECH processes of AM, which assumed equal linear distribution process of AM from the central (bound and unbound) into the biliary secretion and its transit to the lumen (k2=12.9 h-1). The re-absorption process once the AM returns into the lumen due to the ECH was assumed to be equal to the initial absorption after AM administration (ka1, ka2 and ka3). Inter-individual random effects were associated to V2 (46%), k12 (24%), Ku (13%), ka1 (40%), and ka2-3 (34%), showing a moderate-to-high IIV of PK parameters. The RUV was 46% using an additive error model for log-transformed observations.
Conclusion: a population PK model has been successfully applied to characterize the absorption and ECH processes of different OR formulations of AM in rats by adapting a previously population PK model that accounted for the non-linear and linear distribution processes of AM after IV administration. The population PK model assumes different and linear absorption process for each formulation (solution, suspension and supramicellar solution), demonstrating the contribution of surfactant (Tween 80®) in the improvement of AM oral absorption. A moderate fraction of AM suffers EHC, ranging from 22-30% depending on the type of formulation considered.
References:
[1] Campos-Moreno E., et al. (2007) Population modelling to describe pharmacokinetics of amiodarone in rats: relevance of plasma protein and tissue depot binding. European Journal of Pharmaceutical Sciences, 30, 190-197.
[2] Ahmed MS., et al. (2019) A Supramolecular Nanocarrier for Delivery of Amiodarone Anti-Arrhythmic Therapy to the Heart. Bioconjug Chem, 330(3), 733-744.
Reference: PAGE 29 (2021) Abstr 9883 [www.page-meeting.org/?abstract=9883]
Poster: Drug/Disease Modelling - Other Topics