Phase I study of multiple-dose cefprozil and comparison with cefaclor.
The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after administration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The peak levels in plasma (Cmax) of cefprozil ranged from 5.7 to 18.3 micrograms/ml after oral administration of 250- to 1,000-mg doses. The regression analysis of Cmax on cefprozil dose showed a dose-linear response. The mean Cmax of cefaclor ranged from 15.2 to 16.7 micrograms/ml and did not change significantly on multiple dosing. The overall mean terminal half-life of cefprozil was 1.2 h and was invariant with respect to dose or duration of dosing. The area under the plasma-concentration-versus-time curve from 0 h to infinity (AUC0-infinity) of cefprozil increased in a dose-proportional manner with an increase in dose. The overall urinary recovery (61% of dose) and renal clearance values of cefprozil were generally invariant with respect to dose and duration of dosing. While cefprozil was apparently absorbed less rapidly and achieved lower Cmax values than cefaclor, the AUC0-infinity of cefprozil was nearly twofold greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.
Barbhaiya
R H
RH
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Syracuse, New York 13221-4755.
Shukla
U A
UA
Gleason
C R
CR
Shyu
W C
WC
Wilber
R B
RB
Martin
R R
RR
Pittman
K A
KA
D000328:Adult; D001826:Body Fluids / Q000737:chemistry; D002433:Cefaclor / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D002506:Cephalexin / Q000031:analogs & derivatives*; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D006801:Humans; D008297:Male; D012044:Regression Analysis; D000097670:Cefprozil
D002433:Cefaclor; D002506:Cephalexin; D002511:Cephalosporins; D000097670:Cefprozil