EFFECTS OF RENAL-FUNCTION ON RECAINAM PHARMACOKINETICS AND PHARMACODYNAMICS

Objectives: To investigate the pharmacokinetics and pharmacodynamics o f recainam, an investigational class I antiarrhythmic agent, in subjec ts with various degrees of renal function. Methods: This single-dose o pen-label study was carried out at the Clinical Research Center of the University of Pennsylvania Hospital. Twenty-six volunteers participat ed in the study (group 1, glomerular filtration rate [GPR] <15 ml/min; group 2, GFR 15 to 50 ml/min; group 3, GFR >50 ml/min). After a singl e 400 mg oral dose, plasma samples were collected for the following 48 hours. Recainam pharmacokinetic parameters of apparent volume of dist ribution (V-area/F), apparent clearance (CL/F), elimination rate const ant (k(c)), absorption rate constant (k(a)), lag-time (t(lag)), time t o peak (t(max)), and maximum concentration (C-max) were determined wit h a least-squares regression program. The relationship between recaina m concentrations and electrocardiographic intervals were determined wi th the sigmoidal maximum effect model. Measured GFR was correlated to CL/F with regression analysis. Results: There were no significant diff erences found among groups in k(a), t(lag), t(max), and V-area/F. Sign ificant 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 vers us group 3, p < 0.05), C-max (3.54 +/- 0.81, 1.77 +/- 0.53, and 1.63 /- 0.66 mu g/ml, group 1 versus group 2 and group 1 versus group 3, p < 0.01), and k(c) (0.074 +/- 0.025, 0.137 +/- 0.124, and 0.352 +/- 0.3 00, group 1 versus group 3, p < 0.05). Recainam CL/F was highly correl ated 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. Ther e was a trend (but not statistically significant) of increasing maximu m percentage change in PR interval and the effective recainam concentr ation that produces half of its maximum effect (EC(50)) in group 1. Co nclusion: 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 .