title: Population pharmacokinetics of vernakalant hydrochloride injection (RSD1235) in patients with atrial fibrillation or atrial flutter.
abstract: Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.
authors.affiliation: Astellas Pharma Global Development, Inc, Deerfield, IL, USA.
authors.forename: Zhongping Lily
authors.initials: ZL
authors.lastname: Mao
authors.forename: Robert W
authors.initials: RW
authors.lastname: Townsend
authors.forename: Yuying
authors.initials: Y
authors.lastname: Gao
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wheeler
authors.forename: Helen
authors.initials: H
authors.lastname: Kastrissios
authors.forename: James
authors.initials: J
authors.lastname: Keirns
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000840:Anisoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001281:Atrial Fibrillation / Q000188:drug therapy; D001282:Atrial Flutter / Q000188:drug therapy; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003404:Creatinine / Q000097:blood; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D055815:Young Adult
chemical_list: D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C524581:vernakalant; D003404:Creatinine; D019389:Cytochrome P-450 CYP2D6