Vol.58 No.S-1 March 2010
Phase I study of tazobactam/piperacillin in healthy volunteers
Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, Japan
Abstract
Tazobactam/piperacillin(TAZ/PIPC), a penicillin antibiotic combined with a β-lactamase inhibitor at a TAZ/PIPC ratio of 1:8, was administered to 36 healthy Japanese male volunteers to evaluate TAZ/PIPC pharmacokinetics and tolerability after a single and repeated administration.
(1) Pharmacokinetics
Subjects were intravenously injected with a single TAZ/PIPC doses from 2.25 to 4.5 g over a 5-minute period or in doses from 2.25 to 6.75 g over a 30-minute period. The TAZ half-life ranged from 0.7 to 0.9 hour and that of PIPC from 0.8 to 0.9 hour. Cmax increased dose-dependently. After 5-minute injection of 4.5 g TAZ/PIPC, TAZ Cmax was 49.7 μg/mL and PIPC Cmax 436 μg/mL. After 30-minute drip infusion of 6.75 g TAZ/PIPC, TAZ Cmax was 58.2 μg/mL and PIPC Cmax 380 μg/mL. AUCinf increased with dosage. After 5-minute injection of 4.5 g TAZ/PIPC, TAZ AUCinf was 50.4 μg·hr/mL and PIPC 381 μg·hr/mL. After 30-minute drip infusion of 6.75 g TAZ/PIPC, TAZ AUCinf was 83.4 μg·hr/mL and PIPC 557 μg·hr/mL. CLT of TAZ and PIPC decreased with increasing dose. Dose linearity tests on Cmax and AUCinf of TAZ and PIPC after single TAZ/PIPC administration were measured by power model analysis. Results suggest nonlinear pharmacokinetics for both 5-minute injection and 30-minute drip infusion within the dose ranges examined.
TAZ excretion in urine 12 hours after 5-minute injection ranged from 78.8 to 81.3%, while that of PIPC ranged from 55.2 to 56.7%. TAZ excretion in urine 12 hours after 30-minute drip infusion ranged from 63.5 to 71.2%, while that of PIPC ranged from 46 to 52.9%. Both were excreted mainly as the unchanged drug.
TAZ/PIPC was repeatedly administered at a dose of 4.5 g per infusion, three and four times a day. AUC of TAZ and PIPC on days 6 and 8 were the same as on day 1. TAZ and PIPC showed no accumulation and no change in pharmacokinetics in repeated administration.
(2) Tolerability
The following symptoms and findings were regarded as causally related to TAZ/PIPC and their severities was judged as mild: loose stool (30.6%, 11/36 cases); diarrhea, decrease in blood uric acid (13.9%, 5/36 cases each); abdominal pain (5.6%, 2/36 cases); and headache, thirst, chills, chest pain, hot feeling, salivation hypersecretion, nausea, feeling abnormal, stomach discomfort, and decreased appetite (2.8%, 1/36 cases each). From these observations, TAZ/PIPC (1:8 ratio) was shown to be well tolerated.
Key word
tazobactam/piperacillin, phase I study, pharmacokinetics, safety, intestinal bacterial flora
Received
July 24, 2009
Accepted
February 12, 2010
Jpn. J. Chemother. 58 (S-1): 1-10, 2010
