Differential effect of impaired renal function on the kinetics of clavulanic acid and amoxicillin

Amoxicillin and clavulanic acid are prescribed as a fixed drug combination. The purpose of the present study was to assess the influence of various degrees of renal insufficiency (glomerular filtration rate [GFR], less than 5 to greater than 75 ml/min per 1.73 m2) on the pharmacokinetics of amoxicillin and clavulanic acid following oral (500 and 125 mg of amoxicillin and clavulanic acid, respectively) and intravenous (1,000 and 200 mg, respectively) dosing. The volume of distribution and the systemic availability were independent of the renal function, while the total body clearance and the renal and the nonrenal clearance of amoxicillin and clavulanic acid decreased with decreasing renal function. The decrease in the total body clearance was more pronounced for amoxicillin than for clavulanic acid. This explains the increase in the ratio of the area under the plasma concentration versus time curve of amoxicillin to that of clavulanic acid with decreasing glomerular filtration rate after oral dosing; for example for a GFR of 75 ml/min, the ratio of amoxicillin to clavulanic acid was 4.9 +/- 1.2; for a GFR of 35 to 75 ml/min, 5.3 +/- 2.4; for a GFR of 10 to 35 ml/min, 11.9 +/- 5.8; for a GFR of 5 to 10 ml/min, 13.4 +/- 9.1; and for patients on hemodialysis, 14.7 +/- 5.3. Dosage recommendations are suggested which prevent undue accumulations of amoxicillin while maintaining adequate concentrations of clavulanic acid.