Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function

The disposition of coadministered ticarcillin (3 g/1.73 m²) and clavulanic acid (100 mg/1.73 m²) was examined after a 30-min infusion in 24 noninfected subjects with various degrees of renal function. Noncompartmental pharmacokinetic parameters for the individual compounds were determined from plasma concentrations and urinary excretion rates. All clearances (total, renal, and nonrenal) and urinary recoveries of unchanged drug were found to be linearly related to creatinine clearance (CL(CR)). The steady-state volume of distribution (9.9 and 12.9 liters for ticarcillin and clavulanic acid) approximated the extracellular fluid space and was not related to CL(CR). The half-lives increased with reduced renal function and ranged from 56 to 392 min for ticarcillin and 26 to 266 min for clavulanic acid. The clearances of both drugs decreased proportionately with reduction in renal function, facilitating dosing adjustments based on CL(CR). Calculations of expected steady-state maximum and minimum concentrations in plasma using constant doses and an extended dosing interval related to CL(CR) further rationalized use of the 30:1 drug combination ratio for all patients.