Objectives: To investigate the pharmacokinetics and pharmacodynamics of recainam, an investigational class I antiarrhythmic agent, in subjects with various degrees of renal function.
Methods: This single-dose open-label study was carried out at the Clinical Research Center of the University of Pennsylvania Hospital. Twenty-six volunteers participated in the study (group 1, glomerular filtration rate [GFR] < 15 ml/min; group 2, GFR 15 to 50 ml/min; group 3, GFR > 50 ml/min). After a single 400 mg oral dose, plasma samples were collected for the following 48 hours. Recainam pharmacokinetic parameters of apparent volume of distribution (Varea/F), apparent clearance (CL/F), elimination rate constant (ke), absorption rate constant (ka), lag-time (tlag), time to peak (tmax), and maximum concentration (Cmax) were determined with a least-squares regression program. The relationship between recainam concentrations and electrocardiographic intervals were determined with the sigmoidal maximum effect model. Measured GFR was correlated to CL/F with regression analysis.
Results: There were no significant differences found among groups in ka, tlag, tmax, and Varea/F. Significant differences were found in CL/F (114.4 +/- 32.7, 319.4 +/- 129.2, and 795.9 +/- 341.8 ml/min, group 1 versus group 3 and group 2 versus group 3, p < 0.05), Cmax (3.54 +2- 0.81, 1.77 +/- 0.53, and 1.63 +/- 0.66 micrograms/ml, group 1 versus group 2 and group 1 versus group 3, p < 0.01), and ke (0.074 +/- 0.025, 0.137 +/- 0.124, and 0.352 +/- 0.300, group 1 versus group 3, p < 0.05). Recainam CL/F was highly correlated with GFR (r = 0.67, p = 0.001). Approximately 8.9% +/- 3.8% of a recainam dose was eliminated during a 4-hour hemodialysis period. There was a trend (but not statistically significant) of increasing maximum percentage change in PR interval and the effective recainam concentration that produces half of its maximum effect (EC50) in group 1.
Conclusion: Recainam dosing adjustment is required in renal impairment. Recainam is not dialyzed to a significant extent. Further studies are required to fully characterize the pharmacodynamic profile of recainam.