Effects of renal function on recainam pharmacokinetics and pharmacodynamics.

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.