Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys

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124

The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cm.) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUC>o.) showed a dose-proportional response. The steady-state volume of distribution (V,,) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80%o of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime exhibits linear phannacokinetics in healthy subjects.

Section: Resultssupporting

confidence: 77%

Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects

Barbhaiya

Forgue

Gleason

et al. 1992

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124

“…Pharmacokinetic studies with monkeys indicated that cefepime exhibits linear pharmacokinetics and that glomerular filtration is the major route of elimination of this cephalosporin (7). The results of the present study indicate that the concentrations of cefepime in plasma increased with increasing dose in a dose-proportional manner and doseindependent parameters such as mean residence time, CLT, and CLR remained independent of dose.…”

Section: Discussionsupporting

confidence: 60%

“…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.…”

mentioning

confidence: 99%

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

Barbhaiya

Forgue

Gleason

et al. 1990

Self Cite

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

“…Cefoperazone was included because it has broad-spectrum activity against intestinal anaerobic bacteria and is excreted predominantly in the bile (6); ceftriaxone was included because it is also excreted into the bile (23), but it lacks broad antianaerobe activity. Ceftazidime was studied because it lacks broad antianaerobe activity and, unlike cefoperazone and ceftriaxone, is mainly excreted by the kidney (22); and cefepime was studied because, like ceftazidime, it is mainly excreted by the kidney (9), but its antibacterial spectrum includes gram-positive * Corresponding author. cocci such as Staphylococcus aureus (13,14,25).…”

mentioning

confidence: 99%

Modulation of the intestinal flora of mice by parenteral treatment with broad-spectrum cephalosporins

Ogtrop

Guiot

Mattie

et al. 1991

A study was performed to determine the effect of parenteral treatment with four broad-spectrum cephalosporins (cefoperazone, ceftriaxone, ceftazidime, and cefepime) on the number of aerobic gram-negative rods and on the outgrowth of Candida albicans and a multiresistant strain of Citrobacterfreundii in the feces of mice. The estimated fractions of a parenteral dose that were excreted into the gastrointestinal tract were 0.37 for cefoperazone, 0.11 for ceftriaxone, 0.03 for ceftazidime, and 0.002 for cefepime. All four cephalosporins significantly decreased the number of aerobic gram-negative rods in the feces, and virtually all gram-negative rods were eliminated at high doses of cefoperazone, ceftazidime, and ceftriaxone. Furthermore, at high doses these three compounds led to a significant increase of the outgrowth of resistant Citrobacter freundii. The outgrowth of Candida albicans was increased at high doses of cefoperazone and ceftriaxone, whereas ceftazidime and cefepime did not have this effect. The most profound changes in the gastrointestinal ecology were observed during treatment with high doses of cefoperazone. The results suggest that the colonization resistance of the gastrointestinal tract can be substantially decreased by parenteral treatment with cefoperazone and, to a lesser extent, with ceftriaxone and ceftazidime.Broad-spectrum cephalosporins are frequently used for empirical treatment and for the treatment of gram-negative infections in granulocytopenic patients (15). These compounds possess a powerful in vitro activity against gramnegative bacteria, including Pseudomonas aeruginosa. Most gram-positive bacteria are also considered susceptible.Broad-spectrum cephalosporins may also disturb the anaerobic and aerobic intestinal microflora (1, 2, 5), which can lead to a decrease of colonization resistance to opportunistic pathogens. This may lead subsequently to overgrowth by fungi or multiresistant bacteria, which-especially in granulocytopenic patients-increases the risk of acquiring a nosocomial infection.The degree of disturbance of the intestinal microflora due to the parenteral administration of antibacterial agents is dependent on the intrinsic activity of the antibacterial agent against the indigenous bacteria of the gastrointestinal tract as well as on the pharmacokinetic characteristics of the antibacterial agent determining the concentration of the agent in the gastrointestinal tract.In the present study, the effect of parenteral administration of four broad-spectrum cephalosporins (cefoperazone, ceftriaxone, ceftazidime, and cefepime) on the aerobic gramnegative fecal flora and the colonization resistance of the intestinal tract was determined. These four drugs were chosen for several reasons. Cefoperazone was included because it has broad-spectrum activity against intestinal anaerobic bacteria and is excreted predominantly in the bile (6); ceftriaxone was included because it is also excreted into the bile (23), but it lacks broad antianaerobe activity. Ceftazidime was studied because ...