PHASE-I STUDY OF E1077, A NOVEL PARENTERAL CEPHEM ANTIBIOTIC

The safety and pharmacokinetics of E1077, a new injectable cephem anti biotic, were evaluated in healthy male adult volunteers. In the single -dose studies, 100, 250, 500, 1,000, and 2,000 mg of E1077 were admini stered by intravenous infusion at a constant rate for 60 minutes, then 1,000 mg of the drug by intravenous infusion at a constant rate for 5 minutes. The C-max were 6.4, 15.7 +/- 12.0, 34.7 +/- 4.6, 63.2 +/- 4. 6, 142.7 +/- 5.6, and 131.6 +/- 36.0 (means +/- SD) mu g/mL, respectiv ely, and the C-max and AUC increased linearly with the dose. Plasma co ncentration-time curves were well described by a two-compartment open model. The plasma elimination half life of the drug was 1.88 +/- 0.15 hours. The mean urinary recovery within the first 24 hours was 94.1 +/ - 5.1% of the dose. In the multiple-dose study, 2,000 mg of E1077 was intravenously administered at a constant rate over 60 minutes every 12 hours for 4.5 days (a total of nine times). The C-max after the first and ninth doses were 134.0 +/- 17.4 and 135.5 +/- 15.5 mu g/mL, respe ctively, and trough levels in day 1 and day 5 (at 12 hours after the f irst and ninth administration, respectively) were 2.2 +/- 0.8 and 1.9 +/- 0.4 mu g/mL, respectively. No accumulation of the drug in plasma w as observed. There were no significant differences in plasma levels or in urinary recoveries between the single- and multiple-dose regimens. The ratio of the concentrations of the diastereomers of A and B forms measured in the plasma or urine at each point of measurement was equa l to that of the standard sample, and no difference was observed in th e pharmacokinetics of E1077 between the two diastereomers. The fractio n of the drug bound to plasma protein was independent of the total pla sma concentration and was calculated as 14.5 +/- 2.9%. There were no s ubjective or objective abnormal findings definitely related to the dru g, except that two subjects reported mild feelings of sickness during the infusion.