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Population Pharmacokinetic and Pharmacodynamic Analysis of a Class IC Antiarrhythmic, Pilsicainide, in Patients With Cardiac Arrhythmias

From the Departments of Pharmacotherapy (Mr Ogawa, Dr Takahashi, Dr Echizen) and Biopharmaceutics (Dr Mihara), Meiji Pharmaceutical University, Tokyo; and the Departments of Cardiology (Dr Kishi, Dr Takagi, Dr Nakazawa, Dr Miyake), Pharmacology (Dr Matsumoto, Dr Kobayashi), and Hospital Pharmacy (Dr Masuhara), St. Marianna University School of Medicine, Kawasaki, Japan.

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.

Key Words: Pilsicainide • pharmacokinetics-pharmacodynamics • Brugada syndrome

Address for reprints: Hirotoshi Echizen, MD, PhD, Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.

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