N-Acetylprocainamide kinetics and clinical response during repeated dosing

Abstract

Kinetics of and clinical responses to N-acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24-h ambulatory ECG. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r = 0.94, SEE = 3.6 mg/l). The capability for defining patient-specific estimates for drug disposition with 6 or 7 serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 h-1 .+-. 0.017) and volume of distribution (1.25 l/kg .+-. 0.28) were of the same order as in earlier single-dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not clinically effective in any of the 10 patients, although 2 patients demonstrated a > 70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequntly required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient-specific kinetic models that may have applications to other antiarrhythmic drugs.