Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses

Abstract

In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min itravenous infusion) received each antibiotic, according to*a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 mI/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.Cefepime (BMY-28142; Bristol-Myers Squibb Co.) is a "fourth-generation" cephalosporin antibiotic with significant potential advantages over other broad-spectrum cephalosporins and some nontraditional beta-lactam antibiotics (4, 9, 18). It differs from other aminothiazolyl methoxyimino cephalosporins by having a quaternized N-methyl pyrrolidine moiety attached to the methylene group at C-3 (Fig. 1). In addition to a very broad antimicrobial spectrum, cefepime appears to have low affinity for major chromosomally mediated ,3-lactamases and thus is less affected by the nonhydrolytic barrier mechanism of resistance in these bacteria (14). These in vitro advantages have been borne out in a number of in vivo infection models (9,17).Preclinical safety evaluation and pharmacokinetic studies of cefepime were done primarily with rats and monkeys. The findings of these studies suggest that when administered by intravenous infusion, cefepime is as safe as other commercially available cephalosporins. The pharmacokinetics in rats and monkeys have been extensively characterized (2, 7). The present phase I study was designed to evaluate the safety, tolerance, and pharmacokinetics of cefepime in healthy male volunteers. MATERIALS AND METHODSStudy design. The purposes of this study were to evaluate the safety and tolerance of cefepime after single intravenous doses of 62.5, 125, 250, 500, 1,000, and 2,000 mg to normal human volunteers. The pharmacokinetics of cefepime were also assessed at each dose level. The study was

Bioequivalence study of cefepime intramuscular injection

“…The current study showed that the pharmacokinetic parameters for the test formulation, Cefamax, and the reference formulation, Maxipime, are not significantly different, except for CL The pharmacokinetic parameters for Cefamax obtained from the current study were higher than the results from a previous study [2,5,6], which may be the result of the lower body weight of the volunteers in this study. Thus, the drug concentrations of Cefamax were higher than recommended levels for treatment of the infections for which this substance is approved.…”

“…All subjects had good tolerance and no serious adverse events were observed. Conclusion: Cefamax 1 g intramuscular formulation is bioequivalent to Maxipime 1 g intramuscular formulation based on 90% CIs for C max, AUC [0][1][2][3][4][5][6][7][8][9][10][11][12] , and AUC 0-∞ within 80%-125%. …”

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

“…In addition, cefepime appears to have a low affinity for chromosomally derived P-lactamases (23). Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4,5) or intramuscular (9) routes of administration. The pharmacokinetics of this cephalosporin are linear (4,5,9).…”

“…Clinical experience indicates that cefepime is safe and well tolerated when single or multiple (every 8 or 12 h) doses of 250 to 2,000 mg are given by the intravenous (4,5) or intramuscular (9) routes of administration. The pharmacokinetics of this cephalosporin are linear (4,5,9). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4,5,(7)(8)(9).…”

“…The pharmacokinetics of this cephalosporin are linear (4,5,9). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4,5,(7)(8)(9).…”