Pharmacokinetics of cefepime in subjects with renal insufficiency

103

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL CR ) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C min ). C min in this group was found to be 3.3 ؎ 3.6 mg/liter (mean and standard deviation), compared to 19.5 ؎ 21.5 mg/liter in patients with a CL CR of between 60 and 100 ml/min (P ‫؍‬ 0.025) and 14.0 ؎ 11.5 mg/liter in patients with a CL CR of <60 ml/min (P ‫؍‬ 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL CR were highly correlated (P ‫؍‬ 0.00033) according to the equation CL‫؍‬ 0.324 liters/h ؉ (0.0551 ؋ CL CR ). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h ؊1 , respectively. The time-concentration profiles for 1,000 patients (CL CR s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C min that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs <2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are >4 mg/liter), particularly when CL CR exceeds 120 ml/min.Cefepime is a parenteral fourth-generation cephalosporin antibiotic with an extended spectrum of antimicrobial activity. It is active against many gram-positive and gram-negative bacteria, including most members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus (12,13). It is excreted primarily unchanged in the urine. The terminal half-life (t 1/2 ) in plasma is approximately 2 h in normal renal function and increases proportionately to 13.5 h as renal function declines toward anuria. A good correlation has been demonstrated between cefepime clearance (CL) and creatinine clearance (CL CR ) in healthy volunteers with various degrees of renal function (1-4). Dosage adjustment for renal insufficiency has been recommended in order to prevent drug accumulation, which may result in a higher incidence of adverse drug events and/or an unnecessary increase in drug costs (9).The dosage adjustment recommended is primarily based on the proportional decrease in the rate of elimination and healthy volunteer data. However, modification of the dosing regimen based on renal impairment should also take into consideration pharmacodynamic parameters predicting clinical outcome (17). In vitro data have suggested that the bactericidal activity of ␤-lactams is generally concentration independent and that there is a lack of a postantibiotic effect against gramnegative bacteria (8,19). Time abov...

Section: Resultsmentioning

confidence: 96%

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of Cefepime in Patients with Various Degrees of Renal Function

Tam

McKinnon

Akins

et al. 2003

103

“…It is likely that the CLR of cefepime, like that of ceftazidime (16,26), occurs by glomerular filtration, with negligible tubular secretion (1,3,5). A drug disposition study using radiolabeled cefepime clearly indicated that this cephalosporin undergoes minimal metabolism and is excreted primarily as an unchanged drug in urine in humans with normal kidney functions (4).…”

Section: Discussionmentioning

confidence: 99%

“…As a result, cefepime has shown excellent efficacy in treating experimental bacteremia and meningitis caused by Escherichia coli, group B streptococci (19), and pneumococci (29). The excellent spectrum of cefepime, its resistance to the Cefepime is cleared primarily by urinary excretion in unchanged form in animals (2, 10, 11) and humans (1,(3)(4)(5). In the single-dose phase I evaluation, limited blood samples were obtained for the preliminary assessment of pharmacokinetics (1).…”

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confidence: 99%

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

Barbhaiya

Forgue

Gleason

et al. 1992

120

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.

“…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).…”

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confidence: 99%

Lack of pharmacokinetic interaction between cefepime and amikacin in humans

Barbhaiya

Knupp

Pfeffer

et al. 1992

The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 ,g/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin therapy were not significantly altered. Similarly, the pharmacokinetic parameters of amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.Cefepime (BMY-28142) is a new parenteral cephalosporin with significant potential advantages over other new cephalosporins and nontraditional ,3-lactam antibiotics with respect to its antimicrobial spectrum of activity (12,15). 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). Over 80% of the administered dose of cefepime is recovered in urine in an unchanged form (4, 5, 7-9).In the most severely infected patients, empiric therapy consists of the administration of antibacterial therapy before pathogen identification. The standard approach has been to use an ant...