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Mechanism‐based modeling of the effects of ibutilide (IB) on ventricular repolarization in patients with atrial fibrillation (AF)
Author(s) -
Overholser B. R.,
Tisdale J. E.,
Cariera B. L.,
Sowinski K. M.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.369
Subject(s) - ibutilide , qt interval , cardiology , repolarization , medicine , atrial fibrillation , cardioversion , long qt syndrome , ventricular repolarization , anesthesia , electrophysiology
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