Population pharmacokinetic–pharmacodynamic analysis of vernakalant hydrochloride injection (RSD1235) in atrial fibrillation or atrial flutter

Vernakalant hydrochloride is a novel, relatively atrial-selective antiarrhythmic agent that rapidly converts atrial fibrillation (AF) to sinus rhythm (SR). This analysis integrates pharmacokinetic (PK) and safety data from 5 clinical trials of patients with AF or atrial flutter (AFL). Patients were initially given a 10-min intravenous (IV) infusion of vernakalant 3 mg/kg or placebo. If SR was not evident after a 15-min observation, then a second 10-min IV infusion of vernakalant 2 mg/kg or placebo was given. Population pharmacokinetic/pharmacodynamic (PK/PD) models were constructed for QT interval prolongation corrected for heart rate by Fridericia’s formula (QTcF) and for changes in systolic blood pressure (SBP). The exposure–response relationships for QTcF and SBP were best described by sigmoidal maximum-effect ( E max ) models. For QTcF, the model was characterized by a typical E max of 20.3 ms, and by a vernakalant median effective concentration dependent ( EC 50 ) on conversion status (4,222 ng/ml for patients converting to SR and 2,276 ng/ml for those remaining in AF/AFL). For SBP, the model was characterized by E max of 3.05 mmHg and EC 50 of 1,141 ng/ml. Risk of hypotension (SBP