Tazobactam/piperacillin (TAZ/PIPC): Phase I clinical trial

A phase I clinical trial of tazobactam/piperacillin (TAZ/PIPC) was carried out in healthy adult male volunteers. TAZ/PIPC is a combination antibiotic consisting of tazobactam (TAZ), a novel β-lactamase inhibitor, and piperacillin (PIPC) at the ratio of 1:4. To evaluate the tolerance and pharmacokinetics of TAZ/PIPC, the trial was conducted according to the following administration protocols: single intravenous drip infusion (TAZ/PIPC: 1.25 g, 2.5 g and 5.0 g, PIPC: 2.0 g, TAZ: 0.5 g), single intravenous injection (TAZ/PIPC: 1.25 g, 2.5 g), and nine times repeated intravenous drip infusion (5.0 g, twice a day). The results were as follows: 1) Concerning the subjective and objective symptoms, and the results of physical examination and clinical laboratory examination, no change due to the administration of the drug was observed in the single administration test, while in the nine times repeated administration test, diarrhea and headache, cenesthopathia, and thoracalgia were observed in one case. However, these symptoms disappeared without any treatment. 2) The plasma concentrations of TAZ and PIPC increased according to the dose. 3) The plasma half-life (T( 1/2 )β) of both TAZ and PIPC ranged from 0.6 to 0.8 hours. The distribution volume at the steady state and the total clearance of TAZ and PIPC were almost equivalent, indicating that the pharmacokinetics of TAZ and PIPC were similar. 4) The urinary recovery percentage of TAZ, PIPC and M-1, an inactive metabolite, within 24 hours were 67 ~ 77%, 54 ~ 68% and 13 ~ 18%, respectively. 5) The plasma concentration profile and the urine excretion after the nine times repeated intravenous drip infusion of TAZ/PIPC were similar to those of the single infusion. No accumulation was observed after repeated administration of TAZ/PIPC. 6) The total clearance of TAZ after TAZ/PIPC administration was smaller than that of administration with TAZ alone. This showed that the elimination of TAZ was delayed by coadministration with PIPC. 7) No active metabolites of TAZ were detected in plasma and urine, while an active metabolite of PIPC was detected. The metabolite was confirmed to be desethyl piperacillin (DEt-PIPC). On the basis of the above results of the tolerance and pharmacokinetics study, TAZ/PIPC was concluded to be worthy of further clinical evaluation.