Pharmacokinetics of Tazobactam M1 Metabolite After Administration of Piperacillin/Tazobactam in Subjects with Renal Impairment

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many β‐lactamases. The disposition of tazobactam M1 metabolite after intravenous (IV) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4–41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half‐life and area under the plasma concentration—time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3‐ to 4.2‐hour HD session 1 hour after the IV infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36–48 hours after the IV infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n=2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady‐state plasma concentrations of the tazobactam M1 metabolite are 14.6 μg/mL, 34.8 μg/mL, and 48.8 μg/mL for subjects with ClCR 20–40 mL/min (every 6 hour dosing), ClCR