Karine Rodriguez-Fernandez (1), Pablo Calpe (1), Matilde Merino-Sanjuan (1,2), VÃctor Mangas-Sanjuán (1,2).
1 Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Valencia, Spain. 2 Interuniversity Institute of Recognition Research Molecular and Technological Development, Valencia, Spain.
Objectives:
Introduction: 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 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 oral administration.
Objectives: The aim of this study is to quantitatively characterize the pharmacokinetics of AM in rats following different dose levels and routes of administration in order to better understand the mechanisms involved in its absorption and distribution.
Methods: Three different routes of administration were considered: intravenous (IV), oral (OR) and intraperitoneal (IP) of AM. The study design included single (IV, OR and IP) and multiple dosing regimens (IVIV, IVOR, IVIP). The dose levels selected were 12.5 mg (IV and IP), 10 mg (OR), and 25 mg (OR). Each group consisted of eight rats, which were randomly allocated into different groups. AM plasma levels were described with compartmental models assuming linear and non-linear PK processes. Delays in the absorption process and protein binding mechanisms were also considered during the model building analysis. 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: A total number of 88 rats with 883 AM observations were included in the PK analysis. The structural PK model selected assumes a central compartment and a peripheral compartment where the drug is distributed. A non-instantaneous saturable and dynamic plasma protein binding (Amax, Qu and Qb) and linear tissual depot dynamic binding (Qtu and Qtb) were incorporated to account for the AM binding in plasma and in the peripheral compartment, respectively. The maximal amount bounded in plasma was 2.78 mg. A moderate clearance (CL = 0.54 L/h) may explain the short terminal half-life observed for AM (3.8 h). Two depot compartments were considered to account for the different absorption process after OR (CMT=1) or IP (CMT=3) administration. Different bioavailability was considered for each extravasal administration (F1 = 50% and F3 = 54%). A statistical decrease in the OFV (∆OFV = -150) was observed when the absorption process after OR administration was described by a Michaelis-Menten equation (Vmax = 3.86 mg/h and Km = 0.56 mg). The structural model assumes a rapid distribution into the peripheral compartment (Q4 = 1.68 L/h and V4 =1.44 L), acting as depots and causing an important decay in AM plasma levels after dosing.
Conclusions: The pharmacokinetics of AM were successfully described using a two-compartment model with non-linear and linear absorption and linear disposition after oral, intraperitoneal and intravenous administration simultaneously in rats. The intravenous administration allowed to characterize the moderate oral and intraperitoneal bioavailability of AM in rats. A saturable and non-saturable protein-binding mechanisms in plasma and peripheral compartment, respectively, statistically improved the description of the data. The saturable absorption process, which statistically decreased the OFV, should be considered with caution, since only two dose levels (25 and 50 mg) were evaluated and prospective studies will be incorporated to confirm this issue.
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, 30(3), 733-744.
Reference: PAGE () Abstr 9396 [www.page-meeting.org/?abstract=9396]
Poster: Drug/Disease Modelling - Other Topics