Pharmacokinetics of carumonam (AMA-1080) in patients with impaired renal function and in those undergoing hemodialysis

Abstract

The pharmacokinetics of carumonam (AMA-1080) were studied after a single intravenous 1.0-g dose was given to 26 subjects grouped according to their renal functions. Creatinine clearance (CLCR) was above 85, 50 to 84, 10 to 49, and below 10 ml/min/1.73 m2 in groups 1, 2, 3, and 4, respectively. All of the six patients in groups 4 were receiving maintenance hemodialysis, and they were studied both during and between hemodialysis sessions. Carumonam obeyed two-compartment model kinetics in all four group. The volume of distribution based on the area under serum concentration-time curve (Varea) did not differ significantly among the four groups, the mean value being 0.309 +/- 0.084 liter/kg. The elimination-phase (beta) half-lives were 1.53 +/- 0.36, 2.00 +/- 0.64, 5.08 +/- 1.85, and 12.8 +/- 4.1 h in groups 1, 2, 3, and 4, respectively. The 0- to 24-h cumulative urinary recoveries of carumonam were 83 +/- 11, 76 +/- 20, 58 +/- 25, and 12 +/- 9% of the administered dose in groups 1, 2, 3, and 4, respectively. The systemic and the renal clearances of carumonam decreased according to the severity of renal dysfunction, and the nonrenal clearance, which was calculated as the difference between renal and systemic clearances also decreased as CLCR decreased. A significant positive correlation existed between beta and CLCR (r = 0.847, P less than 0.01), and the beta of carumonam could be predicted by the following equation: beta (h-1) = 0.00460 X CLCR (ml/min/1.73 m2) + 0.049. Hemodialysis shortened the elimination-phase half-lives from 12.8 +/- 4.1 to 2.66 +/- 1.49 h in the six subjects in group 4. A 5-h hemodialysis in a hypothetical anephric subject weighing 60 kg was estimated to remove 51.4% of the drug present in the body at the start of hemodialysis.