Abstract 16208: Population Pharmacokinetics of Intravenously and Orally Administered Sotalol in Patients With Cardiac Arrhythmias

Abstract

Introduction: Recently, an intravenous (IV) formulation of sotalol was approved to provide a loading dose before initiating oral sotalol therapy to reduce hospitalization days. However, the population pharmacokinetics (PK) of sotalol after administration of an IV loading dose regimen in patients with atrial fibrillation were not characterized. Understanding the PK of IV sotalol loading dose in patients with atrial fibrillation is required to ensure safety and optimal therapeutic outcomes. Hypothesis: The population PK model of IV and orally administered sotalol can be developed using data from two clinical PK studies with reasonable empirical Bayes estimates (EBEs) of PK parameters absorption rate constant (Ka), clearance (CL), and volume of distribution (Vd). Methods: The PK dataset of sotalol was from: 1) Relative bioavailability study with IV and oral sotalol PK data by sponsor AltaThera Inc., 2) Prospective Evaluation Analysis and Kinetics of IV Sotalol (PEAKS) registry study. Population PK was evaluated using NONMEM® 7.5, Perl-speaks-NONMEM (PsN®) version 5.3.0. Results: 545 sotalol concentrations in 25 patients were analyzed. A one-compartment model with a first-order elimination rate best described the data (Figure 1). The data correlated QTc interval levels within the observed sotalol concentration range (1.2 to 1900 ng/mL) were below 500 ms. In the final model, the EBE’s of sotalol PK parameters were, Ka - 1.44 hr -1 , CL 0.46 - L/h/kg, and the Vd -5.6 L/kg. Further PK/PD studies are needed to establish the correlation between sotalol PK and safety in this population. Conclusions: The PK of sotalol after IV and oral doses were adequately described using a population PK modeling approach. The QTc levels correlated to the plasma concentrations in this study were within the safety limit of 500 ms. This population PK model could be used to correlate the PK with safety (QTc interval prolongation) further to optimize the sotalol IV and oral dosing regimen.