Mechanism‐based modeling of the effects of ibutilide (IB) on ventricular repolarization in patients with atrial fibrillation (AF)

Purpose To characterize the relationship between plasma concentrations of IB and QT prolongation in patients with AF. METHODS: Seven patients requiring direct current cardioversion of AF received a 10 min IV infusion of IB 1.0 mg. Blood samples were collected and plasma IB concentrations were determined by LC/MS. QT intervals were measured from 2 leads (II, V 1 ) and corrected (QT c ) by Bazett and Fredericia methods. PK/PD modeling was performed with ADAPT II and fit simultaneously for both leads. RESULTS: A 2 compartment model best fit the PK data; median (IQ) r 2 =0.95 (0.87,0.99). Plots of actual QT c versus ibutilide plasma concentrations exhibited a counterclockwise hysteresis loop that transformed into a clockwise direction, resembling a rebound phenomenon. A modified indirect response model with zero‐order input and total plasma IB concentrations indirectly driving the inhibition of the output response (i.e. I Kr inhibition with subsequent QT c prolongation) with an additional output rebound response was developed; median (IQ) r 2 =0.80 (0.65, 0.87). The rebound response was initiated at a threshold QT c increase from baseline. The median (IQ) %QT c increase, propagating a rebound response was 11.1% (8.0,14.1) with an IC 50 of 6.4 μg/L (4.7,11.4) for IB. CONCLUSIONS: IB administration for cardioversion of AF prolongs QT c and is indirectly related to total IB plasma concentrations. Additionally, an overcompensating rebound effect was observed leading to a rapid QT c shortening. Clinical Pharmacology & Therapeutics (2004) 75 , P97–P97; doi: 10.1016/j.clpt.2003.11.369