Pharmacokinetics and Safety of Azthreonam in Healthy Japanese Volunteers

抄録

Azthreonam (SQ26, 776), a new, completely synthetic, monocyclic β-lactam antimicrobial agent, was administered to 29 healthy, Japanese male volunteers by intravenous bolus infusion, intravenous drip infusion, and intramuscular injection as single doses, and intravenous bolus infusion as multiple dose. The pharmacokinetics of single intravenous doses of 500 mg, 1000 mg and 2000 mg were best described by a linear open two-compartment model. The mean peak serum levels were proportional to the doses but the mean serum half-life was essentially independent of the dose administered (t_1/2=1.5-1.8h).
The urinary excretion within 24h ranged from 60-70% of the dose administered as intact azthreonam. Usually, intravenous doses were primarily excreted in the 8h urine. The pharmacokinetics of an intramuscular dose of 1000 mg fitted a linear open one compartment model with a mean peak serum level of 66μg/ml at 1h after dosing, and the urinary excretion rate was 80% of the dose administered within 24h. In the multiple dose regimen with 1000 mg of azthreonam administered intravenously to six healthy male subjects every 12h for 5 days, the mean peak serum levels and urinary excretions did not suggest any evidence of drug accumulation. The results of physical examinations and laboratory tests indicated azthreonam was well tolerated with only moderate reversible elevation of CPK values in all subjects at 24h after intramuscular administration.