Phase I study of multiple-dose cefprozil and comparison with cefaclor

Abstract

The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after adiinistration 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 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.

Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration

“…Cefprozil appears to have a significantly longer halflife (t4/2) than cefaclor (2,3). As a result, cefprozil is expected to have higher and more sustained concentrations in plasma than cefaclor in the postdistribution phase.…”

“…Pharmacokinetic studies conducted in humans indicate that cefprozil is well absorbed by the gastrointestinal tract (1)(2)(3). Cefprozil appears to have a significantly longer halflife (t4/2) than cefaclor (2,3).…”

Absolute bioavailability of cefprozil after oral administration in beagles

“…Our data suggest that the absolute bioavailability of cefprozil in dogs is lower than that reported for other oral cephalosporins in humans. Although urinary recovery of cefprozil following oral administration in humans (60 to 70%) is significantly higher (1)(2)(3) than that observed in dogs (40%), the data from this study raise a need to evaluate the fraction of the orally administered dose absorbed and the absolute bioavailability of this new oral cephalosporin in humans.…”

“…Cefprozil, like other oral cephalosporins, is also well absorbed after oral administration (1-3) in humans. However, urinary recovery accounts for about 60% of the administered dose of cefprozil (1)(2)(3). It appears that cefprozil is incompletely absorbed, is metabolized, and/or is eliminated via biliary excretion in humans.…”

“…A 5.0-ml portion of the urine sample was then transferred to a polypropylene tube containing 5.0 ml of sodium acetate buffer (pH 3.6), mixed, and stored at or below -20°C. Plasma and urine samples were assayed for intact cefprozil by using a validated high-performance liquid chromatographic assay with UV detection (2). The lower limits for quantitation of cefprozil in plasma and urine were 0.5 and 2.0 ,ug/ml, respectively.…”