title: 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 (EC₅₀) 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 EC₅₀ 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.
authors.affiliation: Astellas Pharma Global Development US, Inc., 3 Parkway North, Deerfield, IL 60015, USA.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Mao
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Wheeler
authors.forename: Robert
authors.initials: R
authors.lastname: Townsend
authors.forename: Yuying
authors.initials: Y
authors.lastname: Gao
authors.forename: Smita
authors.initials: S
authors.lastname: Kshirsagar
authors.forename: James J
authors.initials: JJ
authors.lastname: Keirns
mesh_terms: D000840:Anisoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001282:Atrial Flutter / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D003198:Computer Simulation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000150:complications; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C524581:vernakalant; D019389:Cytochrome P-450 CYP2D6