title: Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias.
abstract: Population pharmacokinetics (PK) of a sodium channel-blocking antiarrhythmic, pilsicainide, was studied using the nonlinear mixed-effects modeling technique in 91 patients with cardiac arrhythmias (80 suspected Brugada syndrome [BrS] and 11 with atrial fibrillation) who received an intravenous infusion of 10 mg of the drug. Population pharmacodynamic (PD) analysis was also performed using an effect compartment model. PD responses were assessed by changes in electrocardiogram (ECG) pattern (BrS-like elevation of ST-segment) and conduction parameters. The final PK model showed that gender (values were 50% lower in women than in men) and creatinine clearance were significant (P < .01) covariates of weight-normalized systemic clearance of pilsicainide. Patients who showed a BrS-like ECG pattern after the drug administration also showed a significantly (P < .01) greater prolongation in His-Purkinje conduction compared to the remaining patients. In conclusion, female gender, renal dysfunction, and the drug-induced BrS-like ECG morphology may be associated with augmented ECG responses to pilsicainide.
authors.affiliation: Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Ogawa
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kishi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mihara
authors.forename: Harumi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takagi
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Keisou
authors.initials: K
authors.lastname: Masuhara
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nakazawa
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Miyake
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Echizen
mesh_terms: D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism; D002037:Bundle-Branch Block / Q000175:diagnosis / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012737:Sex Factors; D026941:Sodium Channel Blockers / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D008012:Lidocaine; C042288:pilsicainide; D003404:Creatinine