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

Abstract

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 <90 mmHg) was primarily associated with low baseline SBP and to a smaller extent with a history of congestive heart failure (CHF); plasma vernakalant concentrations showed a small contribution to the risk of hypotension (relative risk = 1.4 at 4,000 ng/ml), which may be significant with a baseline SBP of <105 mmHg. These results show that vernakalant had a smaller effect on QTcF in patients who demonstrated conversion to SR than those remaining in AF or AFL, and it had a relatively small effect on SBP.